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Edling, Charlotte. "Receptor tyrosine kinase c-Kit signalling in hematopoietic progenitor cells." Doctoral thesis, Umeå : Umeå University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-888.
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Read, Stuart Hamilton. "Production and function of a soluble c-Kit molecule." Title page, abstract and contents only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phr2845.pdf.
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"Research conducted at the Department of Haematology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science."--T.p. Includes bibliographical references (leaves 170-214). Elevated levels of receptor tyrosine kinases have been implicated in carcinogenesis. It is possible that high expression of c-Kit by the leukaemic cell provides them with a growth advantage over their normal counterparts in the bone marrow microenvironment. Thus, a means of inhibiting the interaction of c-Kit on these cells with ligand Steel Factor may remove proliferation and survival signals. Main aim of the study was to produce a biological inhibitor of this interaction and evaluate its ability to prevent ligand Steel Factor from binding to c-Kit on live cells.
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Shulman, Johanna. "Biochemical analysis of activating mutations of the kit receptor tyrosine kinase." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0003/MQ40794.pdf.
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Rosnet, Olivier. "Caractérisation d'un recepteur à tyrosine kinase apparenté à KIT et FMS." Aix-Marseille 2, 1993. http://www.theses.fr/1993AIX22045.
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La classe iii des recepteurs a tyrosine kinase (rtks) constitue une famille de cinq molecules apparentees impliquees dans la croissance et la differenciation de nombreux types cellulaires au cours du developpement et chez l'adulte. Nous avons isole un sixieme membre de cette famille sur la base de ses similitudes de sequence avec le recepteur du colony stimulating factor 1 (csf1) code par le gene fms. Nous l'avons nomme flt3 (fms-like tyrosine kinase 3). Les adncs correspondant aux homologues murin et humain de ce recepteur ont ete clones. Ils ont permis les localisations chromosomiques des genes correspondants sur la bande q12 du chromosome 13 humain et la bande g du chromosome 5 de la souris. Dans les deux especes, le gene flt3 est proche du gene flt1 qui code pour un recepteur endothelial appartenant a la classe iv des rtks. Ces donnees, et les localisations d'autres genes codant pour des molecules apparentees, supposent que l'emergence de cette famille multigenique a fait intervenir, au cours de l'evolution, des phenomenes de cis et trans-duplication. Chez la souris adulte, l'arn messager de flt3 et son produit sont presents, dans le placenta, les gonades, le cerveau, le cervelet et les organes lympho-hematopoietiques. Au cours du developpement, l'expression de flt3 n'a pu etre montree que dans le foie et le thymus embryonnaire. Chez l'homme, son expression semble predominante au niveau tissulaire dans les organes lympho-hematopoietiques et au niveau cellulaire dans les progeniteurs lymphoides et myeloides
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Lermet, Anne. "Synthèse d'inhibiteurs de la protéine à activité tyrosine kinase c-kit de type sauvage et muté." Lyon 1, 2006. http://www.theses.fr/2006LYO10026.
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Cambareri, Antony Charles. "Molecular and cellular studies examining the biological significance of different isoforms of the receptor tyrosine kinase, c-Kit /." Title page, table of contents and abstract only, 2004. http://web4.library.adelaide.edu.au/theses/09PH/09phc174.pdf.
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Baker, Clare V. H. "XKrk1, a c-kit-related receptor tyrosine kinase expressed in Xenopus embryos." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338070.
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André, Catherine. "Les oncogenes c-kit et c-fms : recepteurs a activite tyrosine kinase." Paris 7, 1992. http://www.theses.fr/1992PA077214.
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Les produits des oncogenes c-fms et c-kit, les pdgfra et pdgfrb appartiennent a la sous-classe iii des recepteurs a activite tyrosine kinase (rtk). Leurs genes sont localises par paire chez l'homme et la souris. Nous avons clone et sequence l'oncogene c-kit humain, sa structure genomique est homologue a celle de c-fms; les deux genes: 60 kb pour c-fms, 80 kb pour c-kit, leur structure exons/introns est identique dans le domaine catalytique. L'organisation genomique de c-kit et c-fms, la localisation chromosomique particuliere des genes de la sous-classe iii des rtk, ainsi que leurs fonctions communes, nous ont conduit a emettre l'hypothese selon laquelle ces genes auraient evolue a partir d'un gene ancestral commun, apres cis et trans duplications. Nous nous sommes interesses a l'implication de c-fms et c-kit dans l'hematopoiese. (1) en collaboration avec l'equipe de pierre tambourin (inserm-u. 152, hopital cochin), nous avons mis en evidence, au sein de l'intron 1 de l'oncogene c-fms (m-csfr), un site preferentiel d'integration du retrovirus de friend (f-mulv), implique dans 20% des leucemies myeloblastiques de la souris. (2) nous avons montre l'expression de c-kit dans les progeniteurs myeloides/erythroides et les mastocytes. Actuellement, nous recherchons l'implication de c-kit et de son ligand, kl, dans l'anemie de fanconi et d'autres aplasies, en collaboration avec le pr. Eliane gluckman (service des greffes de moelle osseuse a l'hopital st louis)
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An, Ningfei, Bo Cen, Houjian Cai, Jin H. Song, Andrew Kraft, and Yubin Kang. "Pim1 kinase regulates c-Kit gene translation." BIOMED CENTRAL LTD, 2016. http://hdl.handle.net/10150/622957.
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Background: Receptor tyrosine kinase, c-Kit (CD117) plays a pivotal role in the maintenance and expansion of hematopoietic stem/progenitor cells (HSPCs). Additionally, over-expression and/or mutational activation of c-Kit have been implicated in numerous malignant diseases including acute myeloid leukemia. However, the translational regulation of c-Kit expression remains largely unknown. Methods and results: We demonstrated that loss of Pim1 led to specific down-regulation of c-Kit expression in HSPCs of Pim1(-/-)mice and Pim1(-/-)2(-/-)3(-/-) triple knockout (TKO) mice, and resulted in attenuated ERK and STAT3 signaling in response to stimulation with stem cell factor. Transduction of c-Kit restored the defects in colony forming capacity seen in HSPCs from Pim1 (-/-) and TKO mice. Pharmacologic inhibition and genetic modification studies using human megakaryoblastic leukemia cells confirmed the regulation of c-Kit expression by Pim1 kinase: i.e., Pim1-specific shRNA knockdown down-regulated the expression of c-Kit whereas overexpression of Pim1 up-regulated the expression of c-Kit. Mechanistically, inhibition or knockout of Pim1 kinase did not affect the transcription of c-Kit gene. Pim1 kinase enhanced c-Kit S-35 methionine labeling and increased the incorporation of c-Kit mRNAs into the polysomes and monosomes, demonstrating that Pim1 kinase regulates c-Kit expression at the translational level. Conclusions: Our study provides the first evidence that Pim1 regulates c-Kit gene translation and has important implications in hematopoietic stem cell transplantation and cancer treatment.
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Larrue, Clément. "Régulation de l'expression protéique des récepteurs à activité tyrosine kinase FLT3 et KIT dans les leucémies aigües myéloïdes." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30195.
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Les mutations FLT3-ITD et KITD816V sont fréquemment retrouvées dans les leucémies aiguës myéloïdes où elles sont associées à un pronostic défavorable. Ces deux récepteurs à activité tyrosine kinase (RTK) mutés sont des acteurs clés de la leucémogenèse régulant la prolifération, la survie et la différenciation cellulaire. L'objectif de ce travail de thèse a été d'étudier la régulation de l'expression protéique de FLT3 en réponse aux inhibiteurs du protéasome, le rôle de l'autophagie dans les LAM KITD816V et l'impact du 2-deoxy-D-glucose sur la localisation intracellulaire des récepteurs. Les travaux réalisés ont démontré trois manières originales de cibler des cellules portant les oncogènes FLT3-ITD ou KIT en jouant sur leur dégradation, leur localisation intracellulaire et l'autophagieFLT3-ITD and KITD816V mutations are recurrently found in acute myeloid leukemia, where they are associated with a poor prognosis. These two Tyrosine Kinase Receptors (TKR) are involved in leukemogenesis, regulating proliferation, survival and cell differentiation. The aim of this thesis was to study the regulation of FLT3 protein expression in response to proteasome inhibitors, the role of autophagy in KITD816V-driven AML and the impact of 2-deoxy-D-glucose (2-DG) on the intracellular localization of TKRs. Our studies investigated three original ways to target cells bearing FLT3-ITD or oncogenic KIT mutations playing on their degradation, intracellular localization and autophagy
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Bachet, Jean-Baptiste. "Récepteurs tyrosine-kinase, voies de signalisation et tumeurs digestives." Versailles-St Quentin en Yvelines, 2013. http://www.theses.fr/2013VERS0019.
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Les récepteurs tyrosine kinase (RTK) sont des pro-oncogènes impliqués dans la pathogénèse de nombreuses tumeurs digestives. Nous avons mené plusieurs travaux de recherche translationnelle et fondamentale sur le RTK KIT et les tumeurs stromales gastro-intestinales (GISTs). Les GISTs avec la delWK557-558 et celles avec une délétion emportant les deux résidus tyrosine de l'exon 11 de KIT semblaient avoir le même pronostique. Les GISTs homozygotes étaient par contre plus souvent malignes que les GISTs hétérozygotes. Les GISTs homozygotes seraient secondaires à une perte d’heterozygotie sans perte de matériel génétique. A partir de lignées cellulaires, nous avons démontré que la biologie de KIT dans les cellules hétérozygotes était plus proche de celle des cellules hémizygotes KIT non muté que des hémizygotes KIT muté. Le statut hémizygote/hétérozygote d'une part et la perte ou non des résidus tyrosine de l'exon 11 de KIT d'autre part étaient associés à des profils d'expression d'ARNm et de miARN spécifiques. Enfin, nous avons pu décrire trois familles avec une mutation germinale de l'exon 13 de KIT et proposer des recommandations pour leur prise en chargeReceptor tyrosine kinases (RTKs) are pro-oncogenes involved in the pathogenesis of many gastrointestinal tumors. We conducted several studies of translational and basic research on the RTK KIT and the gastrointestinal stromal tumors (GISTs). GISTs with delWK557-558 and those with a deletion carrying the two tyrosine residues in KIT exon 11 had the same prognosis. Homozygous GISTs appear more often malignant than heterozygous GISTs. We then reported that homozygous GISTs may be secondary to loss of heterozygosity without loss of genetic material. From cell lines, we demonstrated that the biology of KIT in heterozygous cells was closer to that hemizygous unmutated KIT cells that hemizygous mutated KIT. The hemizygous/heterozygous status on the one hand and the loss or non-tyrosine residues of the KIT exon 11 on the other hand were associated with specific expression profiles of mRNA and miRNAs. Finally, we have described three families with a germline mutation in exon 13 of KIT, and we proposed recommendations for their management
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Caruana, Georgina. "The transforming potential and functional analysis of the c-Kit receptor tyrosine kinase and its natural occurring isoforms /." Title page, abstract and contents only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phc329.pdf.
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Thesis (Ph. D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1996.Copy of author's previously published article inserted into back cover pocket. Includes bibliographical references (leaves 157-214).
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Lam, Lily Po Yee. "A transforming mutation induces dimerization and enhances activity of the c-kit soluble tyrosine kinase domain." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq28773.pdf.
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CASTERAN, NATHALIE. "Etude fonctionnelle de deux recepteurs hematopoietiques a activite tyrosine kinase de classe iii : kit et flt3." Paris 7, 1997. http://www.theses.fr/1997PA077100.
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Les recepteurs flt3 et kit appartiennent a la famille des recepteurs a activite tyrosine kinase de classe iii. Cette famille comprend egalement les recepteurs du pdgf et fms. Ils sont constitues d'une region extracellulaire, formee de 5 boucles de type immunoglobuline, d'une region transmembranaire et d'une partie cytoplasmique contenant un domaine kinase interrompu par une region hydrophile, la region interkinase. Flt3 et kit sont exprimes dans les cellules hematopoietiques precoces et ont aussi un role plus tardif dans la differenciation : au niveau des pre-b pour le recepteur flt3 au niveau de la differenciation mastocytaire pour le recepteur kit. Le recepteur murin flt3 a ete clone en 1992. La construction d'un recepteur chimerique comprenant la partie extracellulaire du recepteur pour le csf1 (fms) fusionnee aux domaines intracytoplasmiques de flt3 a permis en l'absence de son ligand de le stimuler par le ligand csf1. Cette chimere exprimee dans differentes lignees cellulaires nous a permis d'obtenir une reponse mitogenique en presence de csf1 et d'etudier les signaux de transduction actives par flt3. Ainsi p85 de la pi3k et grb2 sont associes au recepteur et gap, shc et vav sont phosphoryles mais non associes. Nous avons determine la sequence de fixation de la pi3k : la tyrosine 958. Le recepteur mute pour la tyrosine 958 (substitution en phenylalanine) ne fixe plus la p85 de la pi3k mais n'affecte ni la mitogenicite ni l'internalisation du recepteur. L'expression de la chimere dans des cellules mastocytaires w/w (deficientes dans l'expression du recepteur kit) reconstitue la mitogenicite et la maturation de ces cellules. Cependant, elle ne permet pas l'adhesion a la fibronectine qui reste une fonction specifique de kit. Flt3 semble donc partager des substrats communs a la transduction du signal de kit. Le gene c-kit code pour 2 isoformes kit#s (pour kit short) et kit#l (pour kit long) qui different dans la partie extracellulaire, a proximite de la membrane, par l'addition de 4 acides amines supplementaires pour la forme longue. L'expression de ces 2 isoformes dans les lignees cellulaires ba/f3 et rat 2 et l'etude de ces cellules a mis en evidence une difference de mitogenicite, d'internalisation et de routage cellulaire des 2 recepteurs apres activation. Kit#s a une hypersensibilite au ligand, internalise rapidement et completement, et co-localise avec les lysosomes apres activation. Kit#l est moins sensible au ligand que kit#s, internalise moins rapidement et partiellement. Cette expression residuelle pourrait correspondre a un recyclage du recepteur puisque cette isoforme est retrouvee co-localisee avec les endosomes apres activation. Au cours des cultures de populations ba/f3 infectees par les 2 isoformes de kit, nous avons obtenu une population kit#s independante du ligand dans sa croissance. Le sequencage de la sequence codante a permis de mettre en evidence une deletion de 9 acides amines. La reproduction de cette deletion dans le plasmide retroviral et son introduction dans les lignees cellulaires rat 2 et ba/f3 permet d'observer une capacite transformante in vitro et in vivo des populations exprimant kit#sd.
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Le, Gall Marianne. "Etude fonctionnelle des formes oncogéniques de KIT : Nouvelles stratégies d'inactivation de la signalisation oncogénique KIT." Phd thesis, Université Paris Sud - Paris XI, 2014. http://tel.archives-ouvertes.fr/tel-00993493.
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Lorsqu'il est surexprimé ou activé constitutivement par mutation, le récepteur tyrosine kinase KIT est impliqué dans le développement de pathologies prolifératives comme les mastocytoses, les tumeurs stromales gastro-intestinales (GIST) et certaines leucémies. La voie de signalisation KIT représente donc une cible thérapeutique majeure en oncologie. Le développement d'une nouvelle classe de molécules pharmacologiques appelées inhibiteurs de tyrosine kinase (ITK) est en plein essor. Un exemple majeur d'ITK est l'imatinib qui cible, entre autre, KIT et est efficace dans la plupart des GIST. Cependant, le traitement aux ITK est souvent confronté au phénomène de résistance primaire ou acquise par mutation secondaire. C'est pourquoi nous cherchons à développer de nouveaux composés ciblant KIT ou les voies de transductions activées par ses formes oncogéniques, et ce par 3 approches.Nous avons récemment montré que les mutants oncogéniques de KIT ont une localisation intracellulaire alors que KIT sauvage est exprimé à la membrane. L'inhibition de l'activité kinase des mutants restaure une localisation normale. A partir de cette observation, nous avons créé et validé un test de criblage par cytométrie mesurant la relocalisation de KIT muté à la surface cellulaire. Le criblage d'une chimiothèque nous a permis de sélectionner de nouveaux inhibiteurs de la signalisation KIT actifs sur des lignées cellulaires mutées pour KIT.Nous avons utilisé la technique du phage display pour sélectionner des anticorps au format scFv et VHH spécifiques de la partie intracellulaire de KIT mutant. Lors de leur expression dans le cytosol (on parle alors d'intrabodies), leur fixation au niveau de KIT inhibe soit directement l'activité kinase, soit le recrutement de partenaires de signalisation. Nous avons obtenu des intrabodies de différentes spécificités vis-à-vis des formes de KIT dont la caractérisation fonctionnelle est en cours Les intrabodies inhibiteurs seront utilisés pour cribler des chimiothèques par ELISA. Les molécules chimiques recherchées empêcheront la fixation des intrabodies sur la région intracellulaire de KIT. On sélectionnera donc des molécules inhibant potentiellement l'oncogénicité de KIT.Nous avons développé des anticorps au format scFv-Fc par phage display qui reconnaissent le domaine extracellulaire de KIT. Deux des anticorps sélectionnés inhibent donc la signalisation induite par le SCF. Dans des lignées de leucémie exprimant KIT WT, nous avons montré que l'utilisation de ces anticorps entraîne une diminution de la viabilité cellulaire. De plus, ils diminuent également la prolifération de lignées de leucémie à mastocytes sensibles et résistantes à l'imatinib (HMC11 et HMC12, respectivement). Ils représentent donc des outils thérapeutiques potentiels pour le traitement des pathologies impliquant KIT ainsi que pour contourner la résistance aux ITK de certains mutants.
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Macêdo, Thais Rodrigues. "Comparação da eficácia do mesilato de imatinibe com a vimblastina associada a prednisona no tratamento do mastocitoma canino: estudo clínico, histopatológico, imunohistoquímico e molecular." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/10/10137/tde-05012015-094225/.
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O objetivo deste trabalho foi avaliar a eficácia do mesilato de imatinibe, em comparação com a quimioterapia usual com vimblastina e prednisona, no tratamento do mastocitoma canino e descrever os efeitos colaterais apresentados pelas medicações. Bem como analisar a expressão do VEGF (fator de crescimento endotelial), a relação da expressão do gene c-kit por RT-PCR e marcação imunoistoquímica do KIT com a presença de mutações na justamembrana e a relação desta mutação com a resposta à terapia. Para tanto foram incluídos 29 animais com diagnóstico citológico de mastocitoma, estes animais foram submetidos a tomografia computadorizada para determinação das medidas das formações cutâneas e em seguida divididos em 2 grupos. O grupo 1 foi tratado com o protocolo quimioterápico de vimblastina e prednisona por 12 semanas e o grupo 2 com o mesilato de imatinibe na dose de 10 mg/Kg a cada 24 horas por 8 semanas. A avaliação da resposta ao tratamento foi realizada com mensurações periódicas das formações com paquímetro e nova tomografia ao final do tratamento para mensuração do maior diâmetro e volume tumoral. Um fragmento das formações cutâneas foi coletado antes do início do tratamento para graduação histológica da neoplasia, determinação do índice mitótico e imunomarcação para KIT, VEGF e Ki- 67. Parte do material coletado teve o DNA e RNA extraídos e posterior sequenciamento dos exons 11 do gene c-kit e determinação da expressão deste e do seu ligante por RT-PCR. A toxicidade a medicação foi avaliada segundo as normas do VCOG 1.1.A taxa de resposta do grupo VP foi de 7,7 % e no grupo MI de 28,6%, embora os pacientes tratados com mesilato de imatinibe tenham apresentado maior chance de resposta a terapia, não foi observado diferença entre os dois grupos. Os dois protocolos foram bem tolerados, os pacientes do grupo MI d menor número de efeitos colaterais. O grau histológico, Indice mitótico, padrão imunohistoquimico do KIT, além da quantificação do ki-67 foram homogêneos nos dois grupos e não influenciaram na resposta ao tratamento. A quantificação do VEGF foi mais intensa nos pacientes com remissão parcial e total. Não foi observado relação entre a quantificação do KIT e a expressão do gene c-kit, que foi maior nos pacientes que responderam ao tratamento, porém a associação desta com a resposta a terapia não pode ser determinada. Mutações ativantes no exon11 do gene c-kit não foram identificadas. O tratamento com o mesilato de imatinibe é bem tolerado pelos animais, no entanto este não se mostrou superior ao protocolo padrão de quimioterapia para o tratamento do mastocitoma; este resultado pode ter sido influenciado pelo número de animais incluídos no estudo. Mutações em outros domínios do receptor KIT e a ação do ITK em receptores como do PDGF e o VEGF podem estar relacionados a resposta a esta classe de fármacos observada neste estudo, a despeito da ausência de mutações ativantes no exon 11 do gene c-kit.The objective of this study was to evaluate the efficacy of imatinib mesylate, compared with the usual chemotherapy with vinblastine and prednisone in the treatment of canine mast cell tumor and describe the side effects submitted by medications. Well as analyzing the expression of VEGF (vascular endothelial growth factor), the relationship between the expression of c-kit gene by RT-PCR and immunohistochemical staining of KIT with the presence of mutations in the juxtamembrane and the relationship of this mutation with response to therapy. For both 29 animals with cytological diagnosis of mast cell tumor were included, these animals underwent computed tomography to determine the measured skin formations and then divided into 2 groups. Group 1 was treated with the chemotherapeutic protocol vinblastine and prednisone for 12 weeks and the second group with the imatinib mesylate in a dose of 10 mg / kg every 24 hours for 8 weeks. The assessment of response to treatment was performed with periodic measurements of the formations Caliper and a new computed tomography in the end of treatment to measure the largest tumor diameter and volume. A fragment of skin formations was collected before the initiation of treatment for histological grading, determination of mitotic index, KIT and VEGF staining patterns and the proliferation marker Ki67. Part of the collected material was extracted RNA and DNA and subsequent sequencing of 11 exons of the c-kit gene and determination and expression of its ligand by RT-PCR. The medication toxicity was evaluated according to the standards of VCOG 1.1.A response rate of the VP group was 7.7% and 28.6% MI group, although patients treated with imatinib had a higher chance of response therapy, no difference in response between the two groups was observed. The two protocols were well tolerated, patients in the MI group had a smaller number of side effects. The histological grade, mitotic index, staining patterns KIT, beyond the quantification of Ki-67 were homogeneous in both groups and did not influence the response to treatment. Quantification of VEGF was intensely in patients with partial and total remission. It was no relationship between KIT and quantification of the expression of c-kit gene, which was higher in patients who responded to treatment, but its association with response to therapy cant be determined. Exon11 activating mutations in the c-kit gene were not identified. Treatment with imatinib mesylate is well tolerated by the animals, however this was not superior to standard chemotherapy protocol for the treatment of mast cell tumors; this result may have been influenced by the number of animals included in the study. Mutations in other domains of the KIT receptor and action in ITK receptors as PDGF and VEGF may be related to response to this class of drugs in this study, despite the absence of activating mutations in exon 11 of c-kit gene.
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Klüppel, Michael. "Analysis of regulatory W mutations and the function of the Kit receptor tyrosine kinase in the intestine." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq35208.pdf.
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Chaix, Amandine. "Les spécificités de la signalisation oncogénique par rapport à la signalisation physiologique : le modèle de KIT, un récepteur à activité tyrosine kinase." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22079/document.
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Le système de communication SCF/KIT est impliqué dans le développement et l’homéostasie de plusieurs lignages cellulaires. Des dysfonctionnements de la voie sont à l’origine de pathologies affectant ces compartiments. En particulier, des mutations gain-de-fonction, qui entraînent l’activation constitutive du récepteur à activité tyrosine kinase KIT, sont responsables de néoplasies chez l’homme.L’objectif des travaux réalisés durant cette thèse était d’étudier certaines spécificités de la signalisation de formes oncogéniques de KIT, ceci dans le modèle du mastocyte transformé par l’oncogène KIT-D816V. Cette étude a été menée au niveau proximal sur le récepteur lui-même ainsi qu’au niveau distal sur la voie STAT ,une des voies de signalisation spécifiquement activée de manière constitutive par le récepteur mutant.Au niveau proximal, nous avons pu montrer que le motif dityrosine Y568-Y570situé dans le domaine juxtamembranaire de hKIT est une plateforme majeure de recrutement des effecteurs de la signalisation intracellulaire avec au moins 15partenaires différents recrutées. Par ailleurs l’étude de modèles cellulaires dans des analyses liées aux fonctions physiologiques du récepteur réalisés in vitro et in vivo ont révélé que le site est impliqué dans la régulation négative du signal transformant issu de l’oncogène KIT-D816.Au niveau distal, nous avons analysé les mécanismes de phosphorylation des protéines STAT1, -3 et -5 ainsi que l’importance fonctionnelle de leur activation dans la transformation dépendante de KIT-D816. Nous avons ainsi étudié la contribution de différentes kinases dans les phosphorylations activatrices des STATs sur tyrosine et serine. Nos résultats suggèrent que seul STAT5 a une activité transcriptionnelle dans nos modèles suggérant une implication potentielle non canonique des STAT1et -3 dans la transformation dépendante de KIT-D816.L’ensemble de nos travaux contribue à une meilleure compréhension des mécanismes de l’oncogenèse dépendante de KIT-D816, un point critique dans le développement raisonné de thérapeutiques anticancéreuses cibléesThe receptor tyrosine kinase KIT and its ligand, the stem cell factor (SCF), are implicated both in the development and the homeostasis of multiple cell lineages. Dysfunctions in the KIT/SCF pathway are involved in several pathologies affecting these compartments. In particular, gain-of-function mutations that lead to constitutive activation of the receptor KIT are found in human neoplasia.The purpose of this thesis project was to investigate some differences between normal and oncogenic signalling of KIT receptor using mast cells transformed by the KIT-D816 oncogene as a model. This question was analysed at aproximal level on the oncogenic receptor itself and at a more distal level on the STAT signal transduction pathway, which is specifically and constitutively activated by theKIT-D816 mutant.At the proximal level, we show that the juxtamembrane dityrosine motif Y568-Y570 of KIT is the major platform of recruitment of intracellular signalling partnerswith more than 15 interactors found in mast cells. Furthermore, the analysis ofcellular models in both in vitro and in vivo assays related to KIT physiological functions has revealed the negative role of the motif in KIT-D816-mediated cell transformation. At the distal level, we have analysed the mechanisms of phosphorylation ofSTAT1, -3 and -5 proteins and the functional relevance of their activation in KITD816-mediated transformation. We describe the contribution of different kinases inthe phosphorylation of STATs on both serine and tyrosine residues. Our results suggest that only STAT5 is transcriptionaly active whereas STAT1 and STAT3 are not, suggesting a non conventional implication of their activation in celltransformation. Our work contributes to a better understanding of the mechanisms of KITD816-mediated oncogenesis and could be used to improve the rational developmentof new targeted cancer therapies
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Lin, Tzu-yin. "The world according to mast cells the role of Kit in normal and neoplastic canine mast cells /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1189098916.
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Voisset, Edwige. "Etude de l'implication des protéines fes et fer dans la signalisation des recepteurs à activité tyrosine kinase kit et FLT3." Aix-Marseille 2, 2008. http://theses.univ-amu.fr.lama.univ-amu.fr/2008AIX22027.pdf.
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La recherche de nouveaux acteurs de la signalisation du récepteur tyrosine kinase KIT, nous a conduit à étudier les protéines tyrosine kinase cytoplasmiques FES et FER. Trois projets ont émané de cette identification. Une première étude a porté sur le récepteur oncogénique KITD816V (mutant retrouvé chez la majorité des patients atteints de mastocytose). Dans ce contexte, FES est phosphorylée sur tyrosines, reflétant son activation constitutive. De plus, en aval de ce récepteur, FES est un régulateur positif de la prolifération cellulaire et plus précisément, cette kinase est impliquée dans la transition des phases G1/S du cycle cellulaire. Au plan moléculaire, FES n’est pas nécessaire à l’activation de la MAP Kinase p38, mais pour celles des protéines STAT et p70S6K. Alors que l’action de FES sur la phosphorylation des STAT semble dépendante du modèle d’étude, son action sur la p70S6K s’avère toujours être une régulation positive. De plus, en aval de KITD816V, FER n’est pas impliquée dans la prolifération cellulaire. Un deuxième sujet tente de déterminer la ou les fonction(s) de FES dans le contexte du récepteur KITWT. Ainsi, nous avons déjà pu montrer que FES interagissait avec KIT stimulé par son ligand et que selon la même cinétique, FES était activée. Ces deux événements sont d’une part, relativement tardifs et d’autre part, transitoires. D’un point de vue fonctionnel, FES et FER interviennent dans le chimiotactisme en réponse au SCF mais pas dans la prolifération cellulaire. Un troisième travail a été mené sur les rôles des protéines FES et FER en aval du récepteur oncogénique FLT3ITD (mutation majoritaire chez les patients atteints de LAM). Pour ces deux kinases, leurs activations sont dépendantes du contexte oncogénique induit par FLT3ITD. L’absence de FES ou de FER dans le système FLT3ITD provoque une diminution de la prolifération cellulaire. Dans le cas de FER, cet effet est consécutif à des défauts de transition entre les phases G1/S et G2/M du cycle cellulaire. Dans le cas de FES, sa présence semble nécessaire à la survie cellulaire. Au niveau moléculaire, ces deux protéines sont des régulateurs positifs de l’activation de STAT5 et des protéines en aval de la PI3Kinase. Ces études ont donc conduit à révéler les protéines FES et FER comme des effecteurs indispensables en aval des récepteurs KIT et FLT3.
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Fraser, Lindsay. "Role of the SCF/KIT signalling pathway in embryonic stem cells." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5564.
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Murine embryonic stem (ES) cells are derived from the inner cell mass of the developing embryonic blastocyst. These cells can self renew which allows them to be propagated indefinitely in the laboratory and they can differentiate into cell types derived from all three germ layers. Manipulation of the mouse genome using gene targeting techniques in conjunction with ES cell technology has provided valuable insights into embryonic development and cell lineage specification. KIT is a trans-membrane receptor tyrosine kinase (RTK) that dimerises upon binding to its ligand, stem cell factor (SCF) resulting in the auto-phosphorylation of intracellular kinase domains. This activity is crucial for the transmission of signals from the cell surface to the nucleus. KIT is expressed on stem and progenitor cells of many lineages and defects in the SCF/KIT signaling pathway causes detrimental effects at both the cellular and physiological level. This project aimed to investigate the role of the SCF/KIT signalling pathway during murine ES cell differentiation and survival. To assess the role of SCF/KIT signalling in ES cell proliferation and survival, we knocked out the c-kit gene in mouse ES cells to produce heterozygous (KitW-lacZ/+) and KIT Null (KitW-lacZ/W-lacZ) cell lines. The self renewal and differentiation profile of these cell lines revealed an auxiliary role for SCF/KIT during ES cell self renewal and an absolute role in survival upon in vitro differentiation. This phenotype of apoptosis upon differentiation was recapitulated in wild type E14 ES cells treated with a KIT neutralising antibody (ACK2). Wild type cells that were treated with the JNK inhibitor, SP600125 had a comparable phenotype to KIT null cells indicating that this could be one of the mediators of KIT signalling that has a protective role in the survival of differentiating ES cells. We hypothesised that blocking classical apoptotic pathways might prevent the death on differentiation observed in KIT null cells. However, neither blocking the pro-apoptotic P38 pathway with the chemical inhibitor PD169316 nor over-expressing the pro-survival protein BCL2 in KIT Null cells could prevent their apoptosis upon differentiation phenotype. This strongly suggests that these pathways are not involved in KIT mediated survival of differentiating ES cells. Although compensatory mechanisms are thought to exist for defective KIT signaling in vivo, an absolute role is assigned to KIT during ES cell differentiation. Further analysis of micro array data comparing gene expression from wild type E14 and KIT Null cell lines may reveal the specific mechanisms of KIT mediated survival during differentiation onset.
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Sepulveda, Paulo De. "Etude genetique et moleculaire de c-kit, le gene codant pour le recepteur a activite tyrosine kinase du facteur scf." Paris 7, 1996. http://www.theses.fr/1996PA077130.
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Les mutations aux loci w et steel de la souris affectent le developpement des cellules souches hematopoietiques, des cellules germinales primordiales, des melanoblastes et des cellules interstitielles de cajal. Le proto-oncogene c-kit, qui code pour le recepteur transmembranaire a activite tyrosine kinase kit, est allelique du locus w, tandis que steel code pour le facteur de croissance scf (stem cell factor), ligand de kit. Le couple kit/scf est implique dans la migration, la proliferation et/ou la survie des cibles cellulaires des mutations w et steel. Les souris heterozygotes pour les mutations w#e#i et w#r#i#o ont un pelage depigmente, du a la mort precoce des precurseur des melanocytes. Cependant, 3% des souris portent une tache de reversion, i. E. De phenotype sauvage, sur leur pelage. Nous avons montre que certaines taches resultent de recombinaisons mitotiques entre chromosomes homologues. D'autres taches ne sont pas dues a la perte de l'allele mutant ; une surexpression de c-kit ou une complementation de la mutation par l'activation d'un autre gene pourraient etre en cause. Notre analyse genetique et moleculaire des taches de reversion phenotypique apporte la premiere demonstration de l'existence de recombinaisons spontanees lors des mitoses au cours de l'embryogenese. Ce resultat est en accord avec l'hypothese selon laquelle les recombinaisons mitotiques peuvent initier des tumeurs, tel le retinoblastome. Nous avons egalement isole le gene c-kit murin complet, et caracterise 4. 2 kb de la sequence en amont du gene. Cette sequence est riche en nucleotides g et c, ne contient pas les consensus classiques tata et caat, et porte une activite promoteur: fusionnee au gene rapporteur lacz, elle induit l'expression de b-galactosidase dans des cellules transfectees. Quatre lignees de souris transgeniques portant le transgene kit/lacz ont ete obtenues et les profils d'expression analyses. Les donnees ainsi obtenues indiquent: (i) l'absence des regions regulatrices conferant la tissu-specificite chez l'embryon, (ii) une expression inattendue du transgene dans la partie neurale de la retine, et (iii) une grande sensibilite du transgene aux effets de position. Nous avons tire parti de cette derniere particularite pour tester la potentialite de sequences d'attachement a la matrice (sar) a tamponner les effets de position en transgenese. La recherche des elements cis-regulateurs de c-kit est en cours
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Tonary, Angela Marie. "Expression, regulation, and function of the KIT tyrosine kinase receptor and its ligand, stem cell factor, in human epithelial ovarian cancer." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ58295.pdf.
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VINCENT, STEPHANE. "Interaction entre le recepteur a tyrosine kinase kit et son ligand kl au cours de la meiose chez la souris male." Nice, 1999. http://www.theses.fr/1999NICE5360.
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Les loci w et steel codent respectivement pour le recepteur a tyrosine kinase kit et son ligand kl. Ces deux genes sont impliques dans plusieurs processus au cours du developpement embryonnaire, en particulier pendant la gonadogenese. Dans le testicule adulte, les genes steel et c-kit sont exprimes, respectivement, dans les cellules de sertoli et a differents stades de la differenciation germinale. L'interaction entre ces deux proteines est requise pour une etape precoce de la spermatogenese ; la proliferation des spermatogonies en voie de differenciation. Jusqu'a present, leur possible participation a des etapes ulterieures, en particulier pendant la meiose, n'avait pas ete clairement etudiee chez la souris male. Nous avons tout d'abord etudie la localisation de l'expression des proteines kl et kit dans l'epithelium seminifere : par facs, nous avons clairement montre que le recepteur kit est present a la surface des spermatocytes. Nous avons pu etablir que kl est exprime de facon cyclique dans les cellules de sertoli, au niveau du compartiment adluminal, en contact avec les cellules meiotiques ; les spermatocytes. Par western blot, nous avons montre que le testicule exprime la forme preferentiellement membranaire du ligand (kl2). A l'aide d'un systeme de coculture permettant de supporter la meiose des cellules germinales, nous avons montre qu'un anticorps bloquant anti kit (ack2) inhibe l'apparition de marqueurs haploides. La meme observation a ete faite en presence de proteine kl recombinante, suggerant que l'interaction entre kit et la forme membranaire de kl est requise pour le passage de la meiose, au moins in vitro. Afin de verifier ces resultats in vivo, nous avons genere des souris transgeniques exprimant un antisens kit sous le controle de deux promoteurs meiotiques : pgk2 et sycpl. Dans toutes les lignees independantes obtenues pour chaque construction, avec une penetrance variable, nous avons observe dans le testicule, la presence de cellules geantes multinuclees caracteristiques d'un defaut de la meiose jusqu'a un blocage partiel ou total pendant la meiose. Ces donnees sont en faveur de l'implication de l'interaction entre kit et kl au cours de la meiose chez la souris male. Afin de disposer d'un modele permettant d'analyser plus finement les consequences biologiques de cette interaction, nous avons entrepris de generer un allele conditionnel du locus w en vue de realiser l'inactivation conditionnelle du locus w dans les spermatocytes pachytenes.
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Sardinha, Ruth Andreia Henriques. "Molecular study of therapeutic targets of tyrosine kinase inhibitors in endometrial stromal tumors: molecular and protein expression of kit, PDGFRA and EGFR." Doctoral thesis, Universidade de Évora, 2014. http://hdl.handle.net/10174/11414.
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Estudo molecular dos alvos terapêuticos dos inibidores tirosina cinase em Tumores
do Estroma Endometrial: Expressão Molecular e Proteica de KIT, PDGFRA e EGFR
Os tumores do estroma endometrial (EST) representam 15% dos sarcomas uterinos, e são
caraterizados por recorrências tardias e metástases à distância. O tratamento sistémico
destas neoplasias não está totalmente estabelecido e alguns estudos descrevem respostas
objetivas ao inibidor tirosina cinase (TKI) imatinib, o que sugere uma nova estratégia
terapêutica para estes tumores. Nesse sentido, o presente trabalho teve como objetivo
efetuar uma análise retrospetiva dos possíveis alvos moleculares dos TKI em EST: KIT,
PDGFRA e EGFR. Numa extensa série de EST que incluiu sarcomas do estroma
endometrial de baixo grau (n=52) e sarcomas endometriais indiferenciados (n=13) foi
efetuada a análise mutacional dos exões 9, 11, 13, e 17 do gene KIT, exões 12 e 18 do
gene PDGFRA e exões 18, 19, 20 e 21 do gene EGFR. A expressão proteica de cada
recetor foi avaliada por imunohistoquímica, e a técnica de hibridação in situ por
fluorescência foi utilizada para avaliar o status do gene EGFR. A sobreexpressão proteica
de KIT, PDGFRA e EGFR foi detetada em 2 (3%), 23 (35.4%), 7 (10.8%) dos casos,
respetivamente. Não foram detetadas mutações ativadoras nos genes KIT, PDGFRA e
EGFR, nem amplificação do gene EGFR. Em conclusão, a ausência de expressão
significativa, amplificação e mutações ativadoras nestes recetores tirosina cinase sugere
que é pouco provável que os EST possam beneficiar de terapias como TKI como tratamento
sistémico; ABSTRACT:
Molecular study of therapeutic targets of tyrosine kinase inhibitors in Endometrial
Stromal Tumors: Molecular and Protein Expression of KIT, PDGFRA and EGFR
Endometrial stromal tumors (EST) represent 15% of uterine sarcomas, and are characterized
by late recurrences and distant metastasis. The systemic treatment of these malignancies is
not well established and few reports describe objective responses to tyrosine kinase inhibitor
(TKI) imatinib, which suggest a novel therapeutic strategy for these tumors. Due to these
facts, the present work aimed to perform a retrospective analysis of possible molecular
targets of TKIs in EST: KIT, PDGFRA and EGFR. In a large series of EST, which included
endometrial stromal sarcomas (n=52) and undifferentiated endometrial sarcomas (n=13) the
mutational analysis was performed for exons 9, 11, 13, and 17 of the KIT gene, exons 12
and 18 of the PDGFRA gene and exons 18, 19, 20 and 21 of the EGFR gene. Protein
expression of each receptor was assessed by immunohistochemistry, and fluorescence in
situ hybridization was used to evaluate EGFR gene status. Overexpression of KIT, PDGFRA,
EGFR, was detected in 2 (3%), 23 (35.4%), 7 (10.8%) cases, respectively. Neither activating
mutations in KIT, PDGFRA and EGFR genes nor amplification of EGFR gene was detected.
In conclusion, absence of significant expression, amplification and activating mutations on
these tyrosine kinase receptors suggest that it is unlikely that EST can benefit from therapies
such as TKI on the systemic setting.
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Bernex, Florence. "Etude fonctionnelle de c-kit, le gene codant pour le recepteur a activite tyrosine kinase du facteur scf chez l a souris." Paris 6, 1996. http://www.theses.fr/1996PA066764.
Full textAbstract:
Les mutations aux loci w et steel de la souris affectent le developpement des melanoblastes, des precurseurs des cellules hematopoietiques et des cellules germinales, ainsi que des cellules interstitielles de cajal. Le gene c-kit qui code pour un recepteur a activite tyrosine kinase, est allelique du locus = w, tandis que steel code pour un facteur de croissance le scf (stem cell factor), ligand de kit. Le couple kit/scf est implique dans diverses etapes du developpement des cibles cellulaires des mutations w, telles que survie, proliferation, migration. Une mutation nulle a ete introduite par recombinaison homologue au locus w/kit dans des cellules embryonnaires souches de souris. Le gene lacz a ete insere a la place de l'exonl de ckit, creant un allele nul wlacz. Chez les embryons w#l#a#c#z/+, l'expression du gene lacz mime l'expression normale du gene ckit. Une analyse detaillee de l'expression spatiale et temporelle du gene lacz chez les embryons w#l#a#c#z/+ et w#l#a#c#z/w#l#a#c#z nous a permis de distinguer deux types cellulaires : (1) les cellules exprimant le gene lacz chez l'heterozygote et absentes chez l'homozygote, (2) des cellules exprimant le gene lacz et retrouvees chez l'homozygote. Les icc expriment c-kit au cours de l'embryogenese, kit est donc requis en postnatal. L'expression de c=kit a ete trouvee dans les cellules endotheliales, epitheliales et endocrines.
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Leiras, Pedro Leonardo dos Santos David Torres. "Clínica e cirurgia de animais de companhia: mastocitoma canino." Master's thesis, Universidade de Évora, 2014. http://hdl.handle.net/10174/13513.
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O estágio curricular a que se refere o presente relatório, decorreu entre os dias 1 de Setembro de 2013 e 31 de Janeiro de 2014 no Hospital Veterinário do Baixo Vouga, sob a orientação científica do Dr. Hugo Vilhena. A área clínica com maior representatividade foi a clínica médica (79% dos casos). Na clínica médica, as doenças infecto-contagiosas e parasitárias foram as mais frequentes (16%), seguidas das doenças gastrointestinais e das glândulas anexas (14%). As únicas espécies observadas foram a canina (75%) e felina (25%). O mastocitoma canino é uma das neoplasias caninas mais comuns e a mais frequente na pele, embora possa desenvolver-se em outras localizações. O diagnóstico citológico é geralmente conclusivo. O comportamento biológico do mastocitoma é muito variável e, por isso, é complicado estabelecer o prognóstico. O sucesso do tratamento é muito dependente do seu comportamento biológico; Abstract:
Small animal medicine and surgery
This report describes the activities developed in the externship performed between September 1st, 2013 and January 31st, 2014 in the Baixo Vouga Veterinary Hospital, under the scientific supervision of Hugo Vilhena, DVM. The clinical area more represented was clinical medicine (79%). Within clinical medicine, infectious and parasitic diseases were the most common (16%), followed by the digestive system disorders (14%). The species attended were dogs (75%) and cats (25%).
Canine mast cell tumors are among the most common neoplasias of dogs, and it’s the most frequent of the skin, though it can arise in other locations. Cytological diagnosis is usually conclusive. Mast cell tumors biologic behavior is very variable. Due to that, establishing a correct prognosis may be difficult, and treatment may be unrewarding.
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Tisserand, Julie. "Mise en évidence d'un rôle suppresseur de tumeur pour la protéine tyrosine-kinase FES dans le mélanome." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM5035.
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Le mélanome est un cancer de la peau agressif et au mauvais pronostic. Si de nouvelles solutions thérapeutiques efficaces ont été développées, les taux de réponses sont variables et transitoires. Découvrir de nouveaux mécanismes oncogéniques dans cette pathologie reste donc nécessaire. Durant mes travaux, j’ai pu démontrer que la protéine tyrosine-kinase FES est exprimée dans les mélanocytes normaux. Cette expression est largement perdue dans un panel de lignées cellulaires de mélanome, au niveau protéique et transcriptionnel ainsi que dans des cultures primaires d’échantillons de patients. La perte de FES est due à une hyper-méthylation de son promoteur et est réversible. En ré-exprimant FES de manière stable dans deux lignées cellulaires de mélanomes, j’ai montré que cette réexpression entraînait une diminution des capacités oncogéniques des cellules. De plus, en analysant les données d’une cohorte de mélanomes (TCGA), j’ai pu établir qu’une diminution importante ou une perte d’expression de FES se retrouve dans près de 40% des patients, et qu’elle est corrélée à une hyper-méthylation du gène FES. Les patients ayant une faible expression de FES présentent un moins bon pronostic soulignant l’importance de ce phénomène. Enfin, en croisant un modèle murin déficient pour le gène Fes avec un modèle de mélanome, nous observons que les tumeurs sous fond Fes KO sont plus prolifératives et plus volumineuses.Ainsi, par des analyses in vitro, sur des données de patients ou en croisant des modèles murins, j’ai pu démontrer que FES est exprimée au niveau des mélanocytes normaux et y exerce un rôle de suppresseur de tumeurAmong skin cancers, melanoma is the most aggressive and has the worst prognosis. In the last years, new therapeutic tools have been developed but responses differ between patients and are often transient due to resistance mechanisms. This highlights the need to improve understanding of molecular mechanisms of the disease. During my thesis, I have shown for the first time that FES tyrosine kinase is expressed in normal melanocytes, and that its expression is lost at the protein and RNA levels in most melanoma cell lines. The same result is observed in a panel of 12 patients’ short-term cultures. The lack of expression is due to FES promoter hyper-methylation and can be reverted using a hypomethylating agent. By restoring FES expression in two melanoma cell lines, I observe a decrease of oncogenic properties of the cells. Moreover, the analysis of the TCGA data on melanoma indicate that FES expression is strongly decreased or lost in about 40% of patients, and that this loss of expression is correlated with FES promoter methylation. Importantly, patients with low level of FES mRNA have poor prognosis compared to FES expressing patients. Finally, Fes knock-out mice crossed with an inducible melanoma mouse model indicate that tumors proliferation and size are more important under a Fes KO background.In conclusion, by using melanoma cells in vitro, data from melanoma patients and mouse models, I have demonstrated that FES is expressed in normal melanocytes and clearly plays a tumor suppressor role.in melanoma
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Dos, Santos Cédric. "Activation anormale de la tyrosine kinase Lyn et de la voie PI3K/Akt dans les leucémies aiguës myéloïdes (LAM) et ciblage pharmacologique." Toulouse 3, 2008. http://www.theses.fr/2008TOU30220.
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Les Leucémies Aigües Myéloides (LAM) représentent un groupe hétérogène d'hémopathies clonales caractérisées par un blocage de la différenciation du à des remaniements des facteurs de transcription, et par une prolifération incontrôlée de cellules leucémiques secondaires à l'activation abérrante de protéines clés de transmission des signaux. La voie de signalisation mTOR/S6K/4E-BP1, qui contrôle la traduction protéique, la prolifération, la croissance et l'apoptose, est activée constitutivement dans environ 70% des échantillons primaires de LAM. L'objectif de ce travail a été d'une part de caractériser les mécanismes moléculaires susceptibles de contribuer à l'activation aberrante de ce relais de signalisation et d'autre part d'étudier l'implication des tyrosines kinases dans les LAM. En comparaison des progéniteurs hématopoïétiques normaux de phénotype CD34+, nous avons démontré que les kinases de la famille Src (SFKs), particulièrement Lyn, sont constitutivement activées dans tous les échantillons primaires de LAM, y compris dans la fraction minoritaire CD34+ CD38- CD123+ enrichie en cellules souches leucémiques. L'utilisation d'un inhibiteur pharmacologique et d'un siRNA dirigé spécifiquement contre Lyn dans des cellules primaires de LAM a permis de démontrer que Lyn joue un rôle critique dans la physiopathologie des LAM, et régule notamment l'activité de la voie mTOR/S6K/4E-BP1. Ces travaux placent donc Lyn comme nouvelle cible thérapeutique potentielle dans le traitement des LAM. Nous avons également étudié l'implication possible de certaines voies de survie pouvant être à l'origine de l'activation de mTOR dans les cellules leucémiques, notamment la voie PI3K/Akt comme cela est bien documenté dans les tumeurs solides. .Acute Myeloid Leukemia (AML) is a clonal hematopoietic disorder characterized by an accumulation of immature leukemic cells an by a block in differentiation. The molecular basis of AML is thougt to arise at the hematopoietic stem or committed progenitors level by the acquisition of at least two types of crucial cooperating mutations. Class I mutations, affecting receptor tyrosine kinases and key components of signalling pathways, conferring growth and proliferative advantages, are associated with class II mutations affecting transcription factors, leading to impaired normal differentiation program. The signalling pathway mTOR/S6K/4E-BP1, involved in the control of translation, growth and apoptosis, is found constitutively activated in about 70% of primary leukemic samples. The aim of this study was first to characterize the molecular mechanism of this constitutive activation patwhay and second to check tyrosine kinases involvement in AML. Compared to normal hematopoietic progenitors CD34+, we have shown that Src kinases family members (SFKs), especially Lyn, are constitutively overactivated in all primary leukemic samples tested, including the small contingent of CD34+ CD38- CD123+ cells which is thought to be the leukemic stem cell compartment. By using pharmacological and siRNA approaches, we were able to demonstrate that Lyn plays a major role in the AML pathophysiology, at least by regulating the mTOR/S6K/4E-BP1pathway activity. This work establish Lyn kinase as a relevant new therapeutic target in the treatment of AML. Then, we assessed the putative implication of several transduction pathways acting upstream of mTOR in AML, especially the PI3K/Akt patway as it has been largely described in solid tumors. Compared to normal hematopoietic progenitors, the PI3K/Akt pathway is strongly activated in AML as we found a high level of the PI3K products and the phosphorylation status of Akt on both threonine 308 (Thr 308) and serine 473 (Ser 473) residues. .
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Tinsley, S. P. "To establish the role of mutations in c-KIT tyrosine kinase in the pathogenesis and therapy of core-binding factor-related acute myeloid leukaemia (AML)." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1433249/.
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Haematopoiesis is controlled by complex signal transduction pathways and transcription regulators which may become dysregulated in acute myeloid leukaemia (AML). Activating mutations in FLT3 and c-KIT receptor tyrosine kinases (RTKs) are commonly found in AML and can impact on prognosis. Different types of FLT3 mutations are known to have distinct biological activities and prognostic implications. The presence of c-KIT mutations has been shown to increase the risk of relapse, but there has been no direct comparison of the biological activity of AML specific c-KIT mutations occurring in different receptor domains. In addition to prognostic information, RTKs are attractive potential targets for therapy using small molecule inhibitors. To evaluate their biological activity and response to targeted therapies, human UT-7 cells were transduced with wild-type and mutant c-KIT isoforms - c-KIT-Δ417-419>Y (extracellular domain [ECD]), c-KIT-L576P (juxtamembrane domain [JMD]), c-KIT-D816V and c-KIT-N822K (both in the activating loop domain [ALD). There were intrinsic differences in signal strength between the mutants examined - only c-KIT-Δ417-419>Y and c-KIT-D816V expressing cells had detectable constitutive c-KIT activation and showed ligand-independent growth. The response of transduced UT-7 cells to c-KIT inhibitors was assessed by treating the cells with dasatinib and masitinib. Cells expressing ALD c-KIT mutations were more resistant to dasatinib or masitinib-mediated cell killing in comparison to cells expressing c-KIT mutations in the ECD and JMD. Western blotting revealed that although c-KIT phosphorylation was potently inhibited, there was residual mTOR and/or PI3K/AKT activation in these cells. The resistance to dasatinib observed in c-KIT-D816V or c-KIT-N822K expressing cells could be overcome by co-blockade of c-KIT and PI3K/mTOR and blockade of c-KIT and PI3K/mTOR was synergistic in all c-KIT mutant cell lines at inducing cell death. Blockade of FLT3 and PI3K/mTOR in FLT3-ITD AML cell lines also showed similar results. During the screening of AML cell lines for c-KIT and FLT3 mutations a novel FLT3-T820N point mutation was identified in the ME-1 cell line. Expression of FLT3-T820N in 32D cells constitutively activated FLT3 and conferred ligand-independent growth. 32D FLT3-T820N cells were most sensitive to the FLT3 inhibitor AC220 with regard to growth inhibition, cell killing and decreased phosphorylation of FLT3 compared to FLT3-WT and FLT3-D835Y expressing cells. This work highlights the differences in biological outcomes and TK inhibitor-sensitivity between different RTK mutants found in AML and shows that simultaneous blockade of RTKs and PI3K/mTOR may provide a novel therapeutic approach for specific AML subtypes.
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Paula, Beatriz Quintino Rogado Mendes. "Padrão de expressão do recetor KIT no mastocitoma canino : seleção dos inibidores dos recetores tirosina quinase." Master's thesis, Universidade de Lisboa, Faculdade de Medicina Veterinária, 2018. http://hdl.handle.net/10400.5/16667.
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Dissertação de Mestrado Integrado em Medicina VeterináriaOs mastocitomas representam cerca de 11 a 27% de todas as neoplasias cutâneas malignas do cão. Devido à sua prevalência e comportamento biológico variável, ao custo da terapêutica e ao potencial stress emocional para os tutores, é importante realizar um prognóstico preciso dos mastocitomas cutâneos e selecionar corretamente a abordagem terapêutica mais apropriada. Vários fatores clínicos podem influenciar o curso da doença, no entanto, o fator de prognóstico mais importante é a gradação histológica. As mutações no c-kit e as alterações da expressão do KIT são conhecidas como indicadores de prognóstico negativo em mastocitomas cutâneos caninos. Além disso, animais portadores de mastocitomas com mutações no c-kit ou padrões de expressão anormais do KIT são potenciais candidatos à terapêutica alvo com inibidores dos recetores tirosina quinase (IRTQ). O principal objetivo deste estudo foi selecionar o melhor IRTQ para cada caso, com base no padrão de expressão do KIT. Um objetivo adicional foi a identificação e avaliação de fatores influenciadores de prognóstico, através de associações estatísticas e da análise de sobrevivência. Os 42 casos de animais com mastocitomas investigados foram, inicialmente, distribuídos por sexo, idade, raça, localização, tipo de lesão e grau histológico do tumor e, ainda, padrão de expressão do KIT. A idade do animal mostrou associação significativa com o grau histológico (p=0,0495) e a localização tumoral com o padrão de expressão do KIT (p=0,0271). Além disso, o risco de desenvolvimento de tumores com padrões do KIT atípicos foi superior nos animais com idades superiores a 8 anos, lesões múltiplas e tumores de alto grau histológico. Como bons indicadores influenciadores de prognóstico identificaram-se a idade no momento do diagnóstico (p=0,01) e o grau histológico do tumor (p=0,002). O risco de morte, relacionada com o mastocitoma, foi superior nos animais com tumores com padrões do KIT atípicos. As variáveis que apresentaram impacto significativo no tempo de sobrevivência foram a idade, o grau histológico, o tratamento quimioterápico e o tratamento com IRTQ. Foram, ainda, obtidos melhores resultados nas fêmeas e nos mastocitomas com padrão de expressão 1. Apesar das limitações do estudo, os resultados obtidos podem contribuir para o estabelecimento de um prognóstico e para a escolha da terapêutica a implementar em casos de mastocitoma cutâneo canino.
ABSTRACT - KIT expression in canine mast cell tumour: tyrosine kinase inhibitors selection - Mast cell tumours (MCT) are the most frequently diagnosed malignant skin neoplasm in dogs, representing up to 27% of all canine cutaneous neoplasms. Due to their prevalence and variable biologic behavior, the cost of therapeutics, and the potential emotional stress to owners, it is important to accurately prognosticate cutaneous mast cell tumours and to correctly select the most appropriate therapeutic approach. There are varied clinical factors that may influence the outcome; however, accurate histologic grading remains a cornerstone of MCT prognostication. Mutations in c-kit and altered expression of KIT have been shown to be negative prognostic indicators for canine cutaneous mast cell tumours. Furthermore, those mast cell tumours that have c-kit mutations or abnormal KIT expression are potential candidates for targeted therapy with tyrosine kinase inhibitors. The main goal of this study was to select the best tyrosine kinase inhibitor for each KIT expression pattern. An additional goal was the identification and evaluation of prognosis influencing factors, through statistical associations and survival analysis. The 42 mastocytomas investigated were initially distributed by sex, age, race, location, type of lesion, histological grade and KIT expression. The animal age showed a significant association with the histological grade (p = 0.0495) and the tumor location with the KIT expression (p = 0.0271). In addition, the risk of developing tumors with atypical KIT patterns was higher in animals aged over 8 years, with multiple lesions and tumors of high histological grade. The age at diagnosis (p = 0.01) and the histological grade of the tumor (p = 0.002) showed to be good prognostic indicators. The risk of death related to the mast cell tumour was higher in animals with tumors with atypical KIT patterns. The variables that had a significant impact on survival time were age, histological grade, chemotherapeutic treatment and treatment with tyrosine kinase inhibitors. Better results were also obtained in females and mast cells tumours with expression pattern 1. Lastly, despite the limitations of the study, the results obtained may be useful in establishing a prognosis and in the therapeutic choice in cases of canine cutaneous mast cell tumour.
N/A
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Yang, Ying. "Identification et caractérisation fonctionnelle des mutations du gène C-KIT dans des pathologies mastocytaires humaines et canines." Aix-Marseille 2, 2009. http://www.theses.fr/2009AIX20670.
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La mastocytose humaine et les tumeurs à mastocyte (TMC) canines sont des pathologies mastocytaires très hétérogènes et associées avec des mutations activatrices du gène c-kit. Dans des études prospectives des caractéristiques cliniques et génotypiques de la mastocytose adulte et pédiatrique, nous avons observé que des mutations de c-kit sur le domaine extracellulaire (ECD) et sur le domaine phosphotransférase (PTD) semblent représenter des spécificités de la mastocytose pédiatrique et adulte respectivement. Ensuite, l'analyse des effets biologiques des mutations de c-kit permet de révéler des conséquences fonctionnelles différentes des mutations ECD versus PTD au niveau cellulaire et moléculaire. Enfin, dans une étude de génotypage des TMC canines, nous avons précisé le statut de mutations activatrices de c-kit et élucidé leur rôle causal dans cette pathologie. En conclusion, l'ensemble de ce travail a permis de mieux comprendre la pathogenèse des maladies mastocytaires et pourrait aider à développer de nouvelles stratégies thérapeutiquesHuman mastocytosis and canine mast cell tumors (MCT) are heterogeneous mast cell diseases and associated with c-kit gain-of-function mutations. In two prospective studies of clinical and genotypic feature of adult and pediatric mastocytosis, we have observed that kit extracellular domain mutations (ECD) and phosphotransferase domain mutations (PTD) are specifically linked with pediatric and adult mastocytosis respectively. Then, analysis of biologic effects of kit mutations revealed at a cellular and a molecular level different functional consequences mediated by ECD mutations versus PTD mutations. Finally, in a kit genotyping study of canine MCT, we delineated the status of kit gain-of-function mutations and elucidated its causative role in this disease. In conclusion, our findings gained insight into pathogenesis of mast cell pathologies and could help to develop new therapeutic strategies
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Lennartsson, Johan. "Stem Cell Factor Induced Signal Transduction." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5291-4/.
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Bibi, Siham. "Nouvelles approches thérapeutiques au cours des mastocytoses systémiques avancées KIT D816V+ résistantes aux inhibiteurs de tyrosine kinases." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS551.
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Les mastocytoses systémiques (SM) constituent un groupe hétérogène de maladies rares, caractérisées par l’accumulation anormale de mastocytes malins dans la moelle osseuse et dans d’autres organes extra-cutanés. La majorité des patients avec SM ont une mutation activatrice du gène KIT, le plus souvent la mutation KIT D816V, retrouvée chez plus de 90% de tous les patients. Cette mutation induit l’activation constitutive du récepteur KIT en déclenchant de façon aberrante une cascade de voies de signalisation, dont la voie PI3K/AKT et JAK/STAT5, aboutissant à l’inhibition de l’apoptose et à l’augmentation de la prolifération et de la survie des mastocytes malins. Cependant, l’efficacité des inhibiteurs de tyrosines kinases (ITKs) sur cette mutation est limitée à cause de la résistance et/ou de toxicité liée à un manque de spécificité. Il est donc nécessaire de trouver de nouvelles approches thérapeutiques afin de contourner cette résistance au cours des SM KIT D816V+ avancées. Nous avons utilisé une approche consistant à cibler de façon combinée des molécules activées en aval de KIT D816V, comme AKT et STAT5, par des inhibiteurs pharmacologiques. Ceci nous a permis d’identifier une combinaison synergique entre un inhibiteur d’AKT (GSK690693) et un inhibiteur de STAT5 (BP-1-102). Ces composés sont capables d’inhiber la prolifération des cellules KIT D816V+ seuls ou en combinaison, mais à de très fortes concentrations, malheureusement non utilisables en thérapeutique. Néanmoins, ces premiers résultats ont permis de valider AKT et STAT5 comme cibles potentielles dans le traitement des SM avancées. La seconde approche employée a été de cibler directement le récepteur KIT D816V par des inhibiteurs pharmacologiques. A l’issu d’un criblage, nous avons identifié trois composés - BLU2317, BLU2718 et DCC-2618 - capables d’inhiber sélectivement la phosphorylation de KIT D816V. Ces composés inhibent la prolifération des cellules ROSAKIT D816V et HMC-1.2, et induisent l’apoptose des cellules de façon dose-dépendante. Bien que les effets de ces trois composés soient similaires, DCC-2618 agit à des concentrations plus faibles par rapport aux composés BLU2317 et BLU2718. Afin d’apprécier l’efficacité in vivo de DCC-2618, nous avons d’abord établi un nouveau modèle de SM basé sur l’injection intraveineuse des cellules ROSAKIT D816V-Gluc exprimant la Gaussia luciferase (Gluc) dans des souris NSG. La présence de la Gluc sécrétée par les cellules ROSAKIT D816V-Gluc facilite la mise en évidence de prise de greffe et permet un contrôle précis de la progression de la maladie. Ce modèle reproduit, au bout de 4 semaines, chez toutes les souris greffées, une SM avancée similaire à celle retrouvée chez l’homme, avec atteinte de la moelle osseuse, du sang, de la rate et du foie, tandis que la dégradation de l’état général des souris n’est observée qu’à partir de 12 semaines. Ce nouveau modèle offre suffisamment de temps pour explorer la cinétique de la progression de la maladie et surtout pour effectuer des études pharmacologiques précliniques. L’évaluation de l’effet de DCC-2618 in vivo a été réalisée sur ce modèle. Etonnamment, DCC-2618 n’a pas été capable d’inhiber la progression de la maladie chez les souris traitées, bien qu’atteignant des concentrations élevées dans la moelle osseuse et le plasma des souris traitées. Néanmoins, DCC-2618 s’est montré capable d’inhiber la phosphorylation de KIT dans les cellules issues de la moelle osseuse des souris traitées. En revanche, contrairement aux effets observés in vitro, DCC-2618 a induit une surexpression de phospho-ERK1/2 dans les cellules malignes des souris greffées. Ceci suggère qu’ERK1/2 joue un rôle important dans la résistance au composé DCC-2618 et éventuellement à d’autres ITKs, indépendamment du récepteur KIT. ERK1/2 pourrait donc être une nouvelle cible thérapeutique d’intérêt dans le traitement des SM résistantes aux ITKsSystemic mastocytosis (SM) is a heterogeneous group of rare diseases characterized by abnormal accumulation of malignant mast cells (MCs) in the bone marrow (BM) and other extra-cutaneous organs. The majority of SM patients have an activating mutation in the KIT gene, usually the D816V point mutation, which is found in more than 90% of all patients. This mutation induces constitutive activation of the KIT receptor by triggering a cascade of signaling pathways, including the PI3K/AKT and the JAK/STAT5 pathways, resulting in the inhibition of apoptosis and increased survival and proliferation of malignant mast cells. However, the efficacy of the tyrosine kinase inhibitors (TKIs) on this mutation is limited due to resistance and/or toxicity associated with a lack of specificity. It is therefore critical to find new therapeutic approaches to overcome this resistance to TKIs, particularly for advanced KIT D816V+ SM. In the present thesis, we have used an approach consisting in targeting molecules activated downstream of KIT D816V, such as AKT and STAT5, using pharmacological inhibitors in combination. This allowed us to identify a synergistic combination of an AKT inhibitor (GSK690693) and an inhibitor of STAT5 (BP-1-102). These compounds are able to inhibit proliferation of KIT D816V+ cells, alone or in combination, but at very high concentrations, unfortunately not useful therapeutically. Nevertheless, these initial results have validated STAT5 and AKT as potential targets for the treatment of advanced SM. The second approach used was to target directly the KIT D816V receptor by pharmacological inhibitors. After a large screening, we identified three compounds - BLU2317, BLU2718 and DCC-2618 - which selectively inhibit the phosphorylation of KIT D816V. These compounds inhibit the proliferation of ROSAKIT D816V and HMC-1.2 cells, and induce apoptosis of these cells in a dose-dependent manner. Although the effects of these three compounds are similar, the DCC-2618 compound acts at lower concentrations relative to BLU2317 and BLU2718 compounds. In order to assess the in vivo efficacy of DCC-2618, we first established a new model of SM based on intravenous injection of cells expressing Gaussia luciferase (Gluc), ROSAKIT D816V-Gluc cells, in NSG mice. The presence of the secreted Gluc in ROSAKIT D816V-Gluc cells facilitates the detection of engraftment and allows precise monitoring of disease progression. This model reproduced within four weeks, in all grafted mice, an advanced SM similar to the one found in humans, with neoplastic MCs infiltration in BM, blood, spleen and liver, while the terminal deterioration of the clinical condition of the mice was observed after 12 weeks. Thus, this new in vivo model allows modulating the aggressiveness of the disease by varying the number of injected cells. It provides sufficient time to explore the kinetics of disease progression and especially to conduct preclinical pharmacological studies. We then evaluated the effect of DCC-2618 compound in vivo on this model. Surprisingly, DCC-2618 was not able to inhibit disease progression in treated mice, although it reached high concentrations in the BM and the plasma of treated mice. Nevertheless, we showed that the compound was able to inhibit the phosphorylation of the KIT receptor in cells derived from the BM of treated mice. In addition, contrasting to the effects observed in vitro, DCC-2618 induced an over-expression of phospho-ERK1/2 in the malignant cells of transplanted mice. This suggests that ERK1/2 may play a critical role in the resistance to DCC-2618, and possibly to other TKIs, independently of the KIT receptor. ERK1/2 could thus be a new interesting therapeutic target in the treatment of advanced SM resistant to TKIs
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Fjällskog, Marie-Louise. "Current Medical Treatment of Endocrine Pancreatic Tumors and Future Aspects." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2709.
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We treated 16 patients with somatostatin analogs combined with α-interferon and achieved a biochemical and/or radiological response in 56% (median duration 22 months). We consider this treatment a good alternative for patients who fail during chemotherapy or who do not want to/cannot receive cytotoxic drugs.
Thirty-six patients with neuroendocrine tumors were treated with cisplatin combined with etoposide. Of 14 patients with evaluable EPTs, 50% responded radiologically and/or biochemically (median duration 9 months). We consider this treatment useful as first-line medical treatment in aggressive EPTs or in patients failing prior chemotherapy.
Twenty-eight tumor tissues from EPTs were examined with immunohistochemistry regarding expression of somatostatin receptors (ssts) 1 to 5 on tumor cells and in intratumoral vessels. We found that sst2 and sst4 were highly expressed on tumor cells and in vessels. However, sst3 and sst5 were lacking in half of the tumor tissues and in most of the vessels. Because of the variability in sst expression, we recommend analysis of each individual’s receptor expression before starting treatment.
Endocrine pancreatic tumors (EPTs) are rare with an incidence of 4 per million inhabitants. In the majority of cases they grow slowly, but there are exceptions with very rapidly progressing malignant carcinomas. First-line medical treatment is streptozotocin combined with 5-fluorouracil.
We examined 38 tumor samples regarding expression of tyrosine kinase receptors platelet-derived growth factor receptors (PDGFRs), c-kit and epidermal growth factor receptor (EGFR). We found that the receptors were expressed in more than half of the tumor tissues. Further studies will reveal if tyrosin kinase antagonists can be part of the future treatment arsenal.
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Barete, Stéphane. "Implications des tyrosine kinases dans la physiopathologie et la thérapeutique des mastocytoses." Paris 7, 2012. http://www.theses.fr/2012PA077058.
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Les mastocytoses représentent un ensemble de pathologies hétérogènes par l'accumulation et/ou à l'activation de mastocytes dans divers tissus. Les mastocytes, dérivent de progéniteurs, expriment KIT un récepteur membranaire à activité tyrosine kinase (TK) codé par le proto-oncogène A77", impliqué dans la différenciation et l'activation du mastocyte. Des mutations activatrices situées majoritairement sur l'exon 17 (au codon 816) de KIT sont impliquées dans les mastocytoses. Or, certains adultes (5% à 30%) et enfants (14%) atteints n'ont pas de mutation de KIT trouvée après séquençage (wild type : WT). Une physiopathologie impliquant d'autres TK est alors envisageable. Les formes indolentes de mastocytoses peuvent être traitées par thérapie ciblée, quand le traitement standard est insuffisant, en bloquant KIT WT comme avec Pimatinib. Dans ce travail nous avons décrit des précurseurs des mastocytes et les prévalences des mutations sur des cohortes de patients. Nous avons étudié le transcriptome centrée sur le kinome en recherchant dans les tissus infiltrés (peau et moelle) s'il existait un profil de tyrosine kinase particulier pour les patients WT par comparaison à ceux mutés en 816. Nos résultats ont montré la surexpression de 4 kinases (JAK3, LYN, TEK, IGF1R) dans la peau mutée en KIT 816. Ensuite nous avons rapporté dans deux études, dans les formes indolentes, l'efficacité du masitinib, un nouvel inhibiteur de TK, qui agirait par blocage de la kinase LYN indépendamment du statut mutationnel de KIT. Si les TK peuvent représenter des cibles thérapeutiques pour les mastocytoses avec KIT muté, la physiopathologie des mastocytoses WT reste à explorer par d'autres techniquesMastocytosis is a heterogeneous disorder characterized by an accumulation of proliferative mast cells with activation in various tissues. Derived from progenitors, mast cells express the membrane KIT receptor encoded by KIT proto-oncogene, which is involved in cellular differentiation and activation. KIT activating mutations, mainly in exon 17 (816 codon position), have been involved in mastocytosis, However, mutation after KIT sequencing analysis is lacking for some affected adults (5% to 30%) and children (14%) (wild type: WT). So, one can speculate that others tyrosine kinases might be involved in pathophysiology of WT mastocytosis. Targeted therapy is an option for indolent systemic mastocytosis (ISM) when symptomatic care is inefficient, to block KIT WT signal transduction and/or proliferation as observed with imatinib. In this work, we have described mast cells precursors and mutations' frequencies among patients cohorts. In another work about WT patients, we have searched in inflltrated tissues (skin and bone marrow) to identify a specific kinase profile comparing to mutated patients. In this transcriptomic study, focused on kinome, our results showed up-regulation of four kinases TK (JAK3, LYN, TEK, IGF1R) in KIT 816 skin. We have then observed in two studies in ISM, a similar efficacy of masitinib, a new tyrosine kinase inhibitor, which might block LYN kinase, independently of KIT mutational status. If these TK might open therapeutic targets for mutated patients, WT mastocytosis pathophysiology remains to be investigated with others research tools
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Tabone, Eglinger Séverine. "Étude du proto-oncogène kit dans les tumeurs stromales gastro-intestinales : du patient au modèle cellulaire." Lyon 1, 2008. http://www.theses.fr/2008LYO10039.
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Les tumeurs stromales gastrointestinales (GISTs) sont caractérisées par l'expression et l'activation du récepteur à activité tyrosine kinase KIT. Après une étude rétrospective des caractéristiques cliniques, histologiques et génotypiques de 276 GISTs, nous avons étudié le rôle de KIT dans leur développement. L'analyse directe des échantillons a ainsi permis de : relativiser l'importance de l'isoforme GNNK-, préciser l'origine de la surexpression de KIT et montrer l'existence d'une boucle autocrine avec le ligand. Enfin, le développement d'un modèle cellulaire exprimant deux délétions de KIT fréquemment observées chez les patients, a révélé que ces mutations activatrices conduisaient à un blocage de la maturation et du trafic intracellulaire de la protéine. En conclusion, des caractéristiques cliniques et biologiques des GISTs, nous avons développé un modèle permettant de mieux comprendre leurs mécanissmes de tumorigenèse et qui aidera au développement de nouvelles thérapies ciblées
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Crépin, Ronan. "Génération d'anticorps thérapeutiques par phage display dirigés contre le récepteur de la transferrine et le récepteur Kit." Paris 11, 2010. http://www.theses.fr/2010PA11T081.
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Santos, Leticia Rielo de Moura [UNIFESP]. "Expressão imuno-histoquímica da proteína C-kit no Retinoblastoma." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9626.
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Publico-11857c.pdf: 120525 bytes, checksum: 614bb713dcd2fcace0a691958c4f8ae7 (MD5)Objetivos: C-kit é uma proteína tirosina–quinase transmembrana que possui importante papel na tumorogênese. Com o desenvolvimento de um novo composto, o mesilato de imatinibe, que inibe especificamente os receptores tirosina quinases, o C-kit passou a ser um importante alvo terapêutico. Nosso objetivo é estudar as características histopatológicas do retinoblastoma, a expressão imuno-histoquímica do C-kit neste tumor e correlacionar esta expressão com os principais fatores prognósticos do retinoblastoma. Material e Métodos: Oitenta e quatro blocos de parafina foram selecionados do arquivo do laboratório de patologia ocular Henry C. Witelson, Montreal, Canada. A imunohistoquímica do C-kit foi realizada de modo automatizado e os resultados foram correlacionados com a idade dos pacientes por ocasião do diagnóstico, grau de diferenciação tumoral e presença ou não de invasão de coróide e nervo óptico. O valor de p menor que 0.05 foi considerado estatisticamente significante. Resultados: A expressão imuno-histoquímica do C-Kit foi observada em 33/63 (52.38%) dos espécimes analisados. Apenas 2 dos 13 (15.4%) tumores que não apresentaram invasão de nervo óptico ou coróide foram positivos para C-kit. Por outro lado, a expressão do C-kit foi observada em 31 (62%) dos 50 tumores que apresentaram algum tipo de invasão seja para coróide ou nervo óptico , 26 dos 44 espécimes com envolvimento de coróide (59.9%), e 20 dos 29 com invasão de nervo óptico (68.96%). Quatorze dos 25 espécimes (56%) moderadamente ou bem diferenciados e 19 dos 38 (50%) pouco diferenciados apresentaram positividade para o C-kit. Dos 41 espécimes provenientes de pacientes com idade superior a 1 ano, e dos 14 (42.80%) com idade até 1 ano a expressão do C-kit foi observada em 21 (51,21%) e 6 (42.80%) espécimes respectivamente. Conclusões: Mais da metade dos retinoblastomas estudados expressaram o C-kit . A expressão do C-kit apresenta correlação estatisticamente significante com a a invasão de nervo óptico.
Purpose: C-kit is a transmembrane tyrosine kinase protein thought to play an important role in tumorigenesis. With the development of the compound Imatinib Mesylate which specifically inhibits tyrosine kinase receptors, C-kit has emerged as a potential therapeutic target. This study aims to determine the immunoexpression of C-kit in retinoblastoma and correlate this expression with histopathological prognostic features. Methods: Eighty-four paraffin-embedded enucleation globes of retinoblastoma were collected from the archives of the Henry C. Witelson Ocular Pathology Registry. C-kit immunostaining was used according to the protocol provided by Ventana Medical System Inc., Arizona. Immunoreactivity was correlated with the presence or absence of invasion into the choroid and optic nerve and the degree of tumour defferentiation. Odds ratios were calculated to quantify differences in C-kit expression between tumours with different patterns of invasion. Results: C-kit expression was identified in 33/63 specimens analysed (53.8%).Two of 13 tumours without choroidal or optic nerve invasio (15.4%) were positive for C-kit. C-kit expression was seen in 31 of the 50 tumours with extraretinal invasion (62%, p<0.01), 26 of 44 specimens with choroidal involvement (59.9%, p<0.02), and 20 of the 29 with optic nerve involvement (68.96%, p<0.02). Fourteen of 25 moderate or well-diferentiated specimens (56%) and 19 of 38 undifferentiated specimens (50%) displayed positivity for C-kit (p>0.5). Conclusions: More than half of Retinoblastomas in this study expressed C-kit. The expression of Ckit in these retinoblastomas strongly correlated with histopathological features of worse prognosis including optic nerve and choroidal invasion.
TEDE
BV UNIFESP: Teses e dissertações
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Khan, Tanweera S. "New Diagnostic and Therapeutic Approaches in Adrenocortical Cancer." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4243.
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Thompson, Jennifer Jane. "Canine Mast Cell Tumours: Characterization of Subcutaneous Tumours and Receptor Tyrosine Kinase Profiling." Thesis, 2012. http://hdl.handle.net/10214/3652.
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This work explored features of canine mast cell tumours (MCT) to improve prognosis and to discover potential therapeutic targets. Subcutaneous MCT - a subset of these tumours arising in the subcutis - are usually grouped with cutaneous MCT, but there is evidence that they may be clinically different. The first objective was to develop a grading scheme for subcutaneous MCT. Over 300 canine subcutaneous MCT were evaluated retrospectively and parameters were correlated with clinical outcomes, making this the largest retrospective survival study of these tumours to date.
The results of the study showed that the majority of subcutaneous MCT had excellent outcomes and key prognostic markers were identified (mitotic index, surgical margins and degree of infiltration). A subset of the subcutaneous MCT from the retrospective study was further evaluated to assess the cellular localization of KIT - a receptor tyrosine kinase (RTK) which is dysregulated and constitutively activated in some cutaneous MCT - as well as Ki67, a proliferation marker. In addition, evaluation of mutations of c-KIT, the gene for KIT, was determined for each MCT. Cytoplasmic KIT localization and high Ki67 values were predictive of decreased survival time and time to local reoccurrence, but no c-KIT mutations were detected.
The majority of canine MCT do not appear to depend solely upon KIT for tumour progression and few other RTK targets have been studied in canine MCT. Based on evidence
that vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR) - may play a role in the progression of canine MCT; the expression and distribution of these RTK were evaluated. The results showed that canine MCT have unique expression profiles and activity of KIT, VEGFR2 and PDGFR.
Two novel mast cell tumour cell lines were generated and used to assess signalling of KIT and VEGFR2 in vitro. Stimulatory and inhibitory responses were assessed and found to be different in both cell lines. Both had autophosphorylated VEGFR2 and an autocrine VEGF/VEGFR2 signalling pathway existed for both cell lines. These findings are unique and the first that identify autocrine VEGF signalling as a possible survival mechanism for canine MCT.Pet Trust Foundation, Ontario Veterinary College
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Young, Sonia Marie. "The receptor tyrosine kinase, c-KIT: its involvement in signal transduction and biological response / Sonia Marie Young." 2003. http://hdl.handle.net/2440/21963.
Full textAbstract:
"March, 2003"Ammendments to chapter 9 and a journal article co-authored by the author in back pocket.
Includes bibliographical references (leaves 162-205)
xviii, 211 leaves : ill. (some col.), plates (some col.) ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2003
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Young, Sonia Marie. "The receptor tyrosine kinase, c-KIT: its involvement in signal transduction and biological response / Sonia Marie Young." Thesis, 2003. http://hdl.handle.net/2440/21963.
Full textAbstract:
"March, 2003"Ammendments to chapter 9 and a journal article co-authored by the author in back pocket.
Includes bibliographical references (leaves 162-205)
xviii, 211 leaves : ill. (some col.), plates (some col.) ; 30 cm.
Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2003
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Tamlin, Vanessa Sarah. "KIT Mutations in Australian Canine Mast Cell Tumours and Correlations with Patient Prognostic Factors." Thesis, 2019. http://hdl.handle.net/2440/123488.
Full textAbstract:
Mast cell tumour (MCT) is the most common skin neoplasm in dogs. Accurately predicting MCT behaviour is essential for proper tumour management. Histological tumour grading is useful for canine prognosis and can be supplemented with the mutational evaluation of the CD117 Proto-Oncogene Receptor Tyrosine Kinase gene, KIT. Dogs with MCTs harbouring an internal tandem duplication (ITD) within exon 11 of the extracellular regulatory domain of KIT are more likely to respond to treatment with tyrosine kinase inhibitors. Conversely, MCTs with mutation of the intracellular tyrosine kinase domain are resistant to this class of drugs. KIT exon 11 ITDs are common in almost 50% of histologically high-grade cutaneous MCTs, whereas the prevalence of enzymatic pocket-type mutations was unknown. Therefore, the prevalence of canine MCT KIT gene mutations and their correlation with prognostic influencers were determined herein. An exon 11 ITD mutation prevalence of 10% was determined in a cohort of 239 Australian dogs with cutaneous MCTs. An exon 11 ITD was detected in only one of 41 subcutaneous MCT. KIT mutation profiles were established using AmpliSeq™ Ion Torrent™ next-generation sequencing technology for 95 MCTs from 93 dogs. Non-synonymous KIT mutations and non-coding variants with a predicted gain-of-function effect on Kit protein activity were identified in 51.9% (n = 40/77) of cutaneous MCTs and 44.4% (n = 8/18) of subcutaneous MCTs. Enzymatic pocket-type mutations, predictably conferring tumour tyrosine kinase inhibitor resistance, were detected in 20.8% (n = 16/77) of the cutaneous MCTs. A novel finding of this research is that mutation of the KIT enzymatic pocket domain statistically significantly predicts 12-month canine MCT-related death in multivariable analysis, independent of tumour histological grade. This finding may help identify potentially aggressive MCT cases which would have been otherwise overlooked by evaluation of histological grade alone. Conversely, exon 11 ITD status did not add any prognostically useful information in the multivariable analyses. However, the analyses revealed that Labrador dogs were at risk of developing high-grade MCTs at an old age (≥ 7 years). In addition to dogs, over 30 other species of mammals, birds and reptiles have been documented with mast cell neoplasia. In a cohort of 20 domestic cats with cutaneous MCT, KIT mutations were detected in 60% of cases. KIT-mutant MCTs were not correlated with tumour increased histological grade or mitotic index and hence, KIT mutation identification was not prognostically useful for cats with MCT. KIT mutations were discovered in the neoplastic DNA from two of four related cheetahs diagnosed with mast cell neoplasia. One of the cheetahs with abnormal KIT was euthanised as a result of visceral mastocytosis. The contribution of mutant-KIT to mast cell oncogenesis and disease malignancy is unclear in this case. The implication of KIT in mast cell neoplasia in dogs, cats and other species is apparent. However, the mechanism of mutation and the contribution to mast cell pathogenesis and malignancy remains relatively obscure. Still, the findings herein will improve the use of KIT and genetic testing in canine MCT prognostication.Thesis (Ph.D.) -- University of Adelaide, School of Animal and Veterinary Sciences, 2019
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Smith, Amanda Melanie. "Targeting PP2A activation as a novel therapeutic strategy for receptor tyrosine kinase driven leukaemia." Thesis, 2014. http://hdl.handle.net/1959.13/1043096.
Full textAbstract:
Research Doctorate - Doctorate of Philosophy (PhD)The receptor tyrosine kinases (RTK) c-KIT and FLT3 are overexpressed or mutated in acute myeloid leukaemia (AML) and numerous other cancers. Constitutive activation of these RTKs stimulates downstream kinase signalling cascades including PI3K/Akt, Ras/MAPK, and JAK/STAT, which lead to increased proliferation and leukaemogenesis. Although inhibition of c-KIT with imatinib mesylate (IM) has been successful in treating gastrointestinal stromal tumour (GIST) patients, responses in AML patients have been less favourable, largely due to intrinsically resistant kinase domain mutations. There are currently no clinically available, therapeutic compounds targeting c-KIT or FLT3 in AML. Considering around half of core-binding factor AML express c-KIT mutations and one third of all AML patients express FLT3 mutations, a greater understanding of the signalling pathways regulated by these RTKs is necessary to identify novel targets for improved therapy of these leukaemias. Protein phosphatase 2A (PP2A) is a fundamental cellular signalling molecule that regulates many of the signalling pathways deregulated in leukaemia. PP2A is a heterotrimeric enzyme composed of a catalytic (PP2A-C), scaffolding (PP2A-A) and one of a number of regulatory (PP2A-B) subunits. PP2A is a proposed tumour suppressor, regulated by interaction with regulatory B subunits, or one of a number of endogenous PP2A interacting proteins. The role of functional PP2A inactivation has recently been recognised as a mediator of oncogenic tyrosine kinase driven leukaemia. This thesis is the first to examine the role of PP2A inhibition in c-KIT and FLT3 driven leukaemogenesis. Utilising the FDCP.1 mouse myeloid cell line expressing imatinib-sensitive (V560G) or –resistant (D816V) mutant c-KIT, and the BaF3 murine lymphoblastic cell line expressing constitutively active FLT3-ITD (FLT3 with internal tandem duplication), I show for the first time that constitutive activation of c-KIT or FLT3 induces functional inactivation of PP2A tumour suppressive activity. Importantly, pharmacological reactivation of PP2A by FTY720 or AAL(S) was found to inhibit the growth and survival of cells expressing these mutant RTKs. Furthermore, I have shown that FTY720 mediated activation of PP2A induces apoptosis of AML patient blasts expressing FLT3 mutations, compared to patient cells expressing the WT FLT3 receptor. PP2A inhibition was found to be associated with reduced protein, but not mRNA, expression of PP2A structural and regulatory subunits, and this is functionally important as over-expression of exogenous PP2A-A induced apoptosis in these cells. PP2A inhibition was further associated with the expression of novel variants of the endogenous PP2A inhibitory protein, SET. These novel variants were also identified in AML patient blasts. Further investigations showed that these novel variants alter the subcellular localisation of SET, and its co-localisation with PP2A. Investigations into the mechanism of action of the PP2A activating compound, FTY720, found that FTY720 alters the expression and sub-cellular location of these novel SET proteins, suggesting that they are functionally important in the cellular response to FTY720. Finally, I showed that PP2A activators synergise with clinically relevant tyrosine kinase inhibitors to inhibit colony formation and proliferation. Therefore, the work in this thesis significantly contributes to our understanding of the role of PP2A as a tumour suppressor in AML, and suggests thatPP2A activators present a novel therapeutic strategy for RTK driven leukaemias used as a monotherapy or in conjunction with targeted tyrosine kinase inhibitors.
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Subramanian, Aparna. "The BMP4 stress erythroid pathway and the Kit receptor tyrosine kinase in Friend virus induced erythroleukemia." 2005. http://etda.libraries.psu.edu/theses/approved/WorldWideIndex/ETD-963/index.html.
Full text
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Caruana, Georgina. "The transforming potential and functional analysis of the c-Kit receptor tyrosine kinase and its natural occurring isoforms / by Georgina Caruana." Thesis, 1996. http://hdl.handle.net/2440/18708.
Full textAbstract:
Copy of author's previously published article inserted into back cover pocket.Bibliography: leaves 157-214.
iv, 214, [131] leaves, [19] leaves of plates : ill. (some col.) ; 30 cm.
The function of receptor tyrosine kinase, c-Kit is examined in relation to the role of receptor levels in factor dependence and cell transformation and the function of several naturally occurring isoforms of the human c-Kit receptor were analyzed by expressing cDNA encoding these isoforms in murine cells.
Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1996
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Ming-JungLin and 林明蓉. "Explore the Growth Inhibitory Effect and Mechanisms of Novel Tyrosine kinase Inhibitors on Mutant KIT-expressing Gastrointestinal Stromal Tumor." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/08821740439736135940.
Full textAbstract:
碩士國立成功大學
分子醫學研究所
102
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors of the gastrointestinal tract. GISTs frequently exhibit gain-of-function KIT mutations (70-80% of GISTs), which leads to constitutive activation of the KIT tyrosine kinase receptor in the absence of its binding ligand, stem cell factor (SCF). The most common KIT mutations are located at exon 11 (≈80%) followed by exon 9 (≈10-15%) and exons 13, 14 or 17 (≈5%). Clinically, imatinib mesylate (IM), sunitinib malate (SU), regorafenib, a sorafenib-derived compound, are multi-tyrosine kinase inhibitors (TKIs), are the current standard treatments for patients with unresectable and/or metastatic GIST. However, those drugs have limitations: experience disease progression, associated with the acquisition of secondary mutations, and unsatisfactory median progression-free survival. Therefore, it is important to explore much suitable compound for advanced gastrointestinal stromal tumor. In this study, we aim to evaluate the growth inhibitory effects and molecular mechanisms of a novel TKI from the Institute of Biotechnology and Pharmacology, National Health Research Institutes, the 1J373S1 that was initially designed as a FLT-3 inhibitor, on IM and/or SU resistance GIST cells. The 1J373S1 shows activity on inhibiting the KIT phosphorylation and proliferation of KIT mutated GIST cells, including IM-sensitive exon13 mutated GIST882, IM-resistant/sunitinib-sensitive exon 11/13 doubly mutated GIST430, IM/SU-resistant/nilotinib-sensitive exon 11/17 doubly mutated GIST48. The superiority of 1J373S1 on inhibiting the activation of KIT mutant proteins was confirmed in an in vitro cell-based platform consisting of a series of COS-1 cells expressing various KIT cDNA constructs encoding common primary ± secondary mutations observed in clinical GISTs. Interestingly, TKI treatment usually resulted in G0 arrest in sensitive cell lines (SU for GIST 430 and nilotinib for GIST48), however, 1J373S1 treatment resulted in G2/M-arrest in both GIST48 and GIST430 cells and also induces GIST cell lines apoptosis. In addition, we have explored that 1J373S1 treatment can induce senescent signals: p53, p21, p16, E2F, β-galactosidase signal up-regulation of exon 11/17 doubly mutated GIST48. In future work, we shall explore the molecular mechanisms of growth inhibition GIST cells further more.
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Muirhead, Karla Jaimee. "The role of KL and C-Kit in primordial follicle activation in the juvenile rabbit ovary." Phd thesis, 2005. http://hdl.handle.net/1885/150654.
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Yuan-ShuoHsueh and 薛元碩. "Establishment of a Drug Screening Platform to Study the Effects and Mechanisms of Tyrosine kinase Inhibitors and a Novel HSPAA1 Inhibitor (NVP-AUY922) on Mutant KIT-expression GIST." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/39080318730110331378.
Full textAbstract:
博士國立成功大學
臨床藥學與藥物科技研究所
101
Background Advanced gastrointestinal stromal tumors (GIST), a KIT oncogene-driven tumor, on imatinib mesylate (IM) treatment may develop secondary KIT mutations to confer IM-resistant phenotype. Second-line sunitinib malate (SU) therapy is largely ineffective for IM-resistant GISTs with secondary exon 17 (activation-loop domain) mutations. Nowadays, several KIT tyrosine kinase inhibitors (TKIs) and heat shock protein 90 (HSP90AA1) inhibitors are under investigation for IM and/or SU-resistant GIST patients. However, there is no notable improvement. In this study, we used commercial available TKIs and a new class of HSP90AA1 inhibitor, NVP-AUY922 (AUY922), to evaluate their potencies for treatment on IM and/or SU-resistant GISTs and to clarify the detailed mechanisms. Methods and Results First, we established an in vitro cell-based platform consisting of a series of COS-1 cells expressing KIT cDNA constructs encoding common primary±secondary mutations observed in GISTs, to compare the activity of several commercially available TKIs on inhibiting the phosphorylation of mutant KIT proteins at their clinically achievable plasma steady-state concentration (Css). The inhibitory efficacies on KIT exon 11/17 mutants were further validated by growth inhibition assay on GIST48 cells, and underlying molecular-structure mechanisms were investigated by molecular modeling. Our results showed that SU more effectively inhibited mutant KIT with secondary exon 13 or 14 mutations than those with secondary exon 17 mutations, as clinically indicated. On contrary, at individual Css, nilotinib and sorafenib more profoundly inhibited the phosphorylation of KIT with secondary exon 17 mutations and the growth of GIST48 cells than IM, SU, and dasatinib. Molecular modeling analysis showed fragment deletion of exon 11 and point mutation on exon 17 would lead to a shift of KIT conformational equilibrium toward active form, for which nilotinib and sorafenib bound more stably than IM and SU. In the other hand, we demonstrated that AUY922 is effective in inhibiting the growth of GIST cells expressing mutant KIT protein, the IM-sensitive GIST882 and IM-resistant GIST48 cells. The growth inhibition was accompanied with a sustained reduction of both total and phospho-KIT proteins and the induction of apoptosis in both cell lines. Surprisingly, AUY922-induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway. The blockade of autophagy alone led to the accumulation of the KIT protein, highlighting the role of autophagy in endogenous KIT turnover. The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B-, acridine orange-, or SQSTM1-labeled autophagosome, and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity. In addition, AUY922 could reduce KIT mRNA at transcription level without affecting its mRNA stability. Further studies showed that AUY922 treatment would reduce the nuclear activities and protein levels of several transcription factors, such as CEBP, TP53, RELA, and HIF1A in GIST cells. Experiments using DNA affinity precipitation and chromatin immune-precipitation assays showed that TP53 could bind on KIT promoter region (from -365 to -30 nucleotides upstream of the transcriptional start site), and its binding activity was significantly reduced after AUY922 treatment. Conclusions Taken together, we show that nilotinib and sorafenib are more active in IM-resistant GISTs with secondary exon 17 mutation than SU that deserve further clinical investigation. Moreover, the results of AUY922 not only highlight its potential application for the treatment of KIT-expressing GISTs, but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitor-induced KIT degradation in GIST882 and GIST48 cells.