Letteratura scientifica selezionata sul tema "Oncogene Protein p21(ras)"
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Articoli di riviste sul tema "Oncogene Protein p21(ras)"
1
Lowe, D. G., e D. V. Goeddel. "Heterologous expression and characterization of the human R-ras gene product". Molecular and Cellular Biology 7, n. 8 (agosto 1987): 2845–56. http://dx.doi.org/10.1128/mcb.7.8.2845-2856.1987.
Testo completoAbstract (sommario):
We directly expressed human R-ras 23,000-dalton protein (p23) cDNA in Escherichia coli under the control of the trp promoter. GTP-dependent phosphorylation of a p23 threonine 85 substitution mutant was observed. This result is in direct analogy to the autokinase activity of H-ras and K-ras threonine 59 substitution mutants. Normal p23 protein was detected in the human fibrosarcoma cell line HT1080 by immunoprecipitation with rabbit antibodies raised against an E. coli-expressed R-ras fusion protein. The R-ras p23 protein was found to be 3H labeled in the presence of [9,10(n)-3H]palmitic acid and is associated with the P100 membrane fraction of HT1080 cells. These data suggest that human R-ras p23 has biochemical properties very similar to those of the p21 products of the H-, K-, and N-ras proto-oncogenes. We constructed an R-ras minigene and engineered the expression of normal and mutant alleles from the simian virus 40 early region promoter. Normal and mutant R-ras gene products were authenticated by transient expression in COS-7 cells and immunoprecipitation. The valine 38-substituted R-ras p23 displayed reduced electrophoretic mobility. R-ras p21-like proteins, made by eliminating the first 26 R-ras codons, displayed evident mobility differences between the pro form and mature form, along with a valine 12 substitution-dependent change in electrophoretic mobility. Rat-1 fibroblasts were transfected with normal and mutant R-ras alleles and normal and activated H-ras alleles. Unlike the human T24 bladder oncogene-encoded p21, mutant R-ras alleles do not cause monolayer focus formation or growth in soft agar of rat fibroblasts.
2
Lowe, D. G., e D. V. Goeddel. "Heterologous expression and characterization of the human R-ras gene product." Molecular and Cellular Biology 7, n. 8 (agosto 1987): 2845–56. http://dx.doi.org/10.1128/mcb.7.8.2845.
Testo completoAbstract (sommario):
We directly expressed human R-ras 23,000-dalton protein (p23) cDNA in Escherichia coli under the control of the trp promoter. GTP-dependent phosphorylation of a p23 threonine 85 substitution mutant was observed. This result is in direct analogy to the autokinase activity of H-ras and K-ras threonine 59 substitution mutants. Normal p23 protein was detected in the human fibrosarcoma cell line HT1080 by immunoprecipitation with rabbit antibodies raised against an E. coli-expressed R-ras fusion protein. The R-ras p23 protein was found to be 3H labeled in the presence of [9,10(n)-3H]palmitic acid and is associated with the P100 membrane fraction of HT1080 cells. These data suggest that human R-ras p23 has biochemical properties very similar to those of the p21 products of the H-, K-, and N-ras proto-oncogenes. We constructed an R-ras minigene and engineered the expression of normal and mutant alleles from the simian virus 40 early region promoter. Normal and mutant R-ras gene products were authenticated by transient expression in COS-7 cells and immunoprecipitation. The valine 38-substituted R-ras p23 displayed reduced electrophoretic mobility. R-ras p21-like proteins, made by eliminating the first 26 R-ras codons, displayed evident mobility differences between the pro form and mature form, along with a valine 12 substitution-dependent change in electrophoretic mobility. Rat-1 fibroblasts were transfected with normal and mutant R-ras alleles and normal and activated H-ras alleles. Unlike the human T24 bladder oncogene-encoded p21, mutant R-ras alleles do not cause monolayer focus formation or growth in soft agar of rat fibroblasts.
3
Mandanas, RA, DS Leibowitz, K. Gharehbaghi, T. Tauchi, GS Burgess, K. Miyazawa, HN Jayaram e HS Boswell. "Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells". Blood 82, n. 6 (15 settembre 1993): 1838–47. http://dx.doi.org/10.1182/blood.v82.6.1838.1838.
Testo completoAbstract (sommario):
Abstract The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth- factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence. In these p210 bcr-abl-transformed cells (H7 bcr-abl.A54) and in two other murine myeloid cell lines transformed to IL-3 independence by p210 bcr-abl, endogenous p21 RAS is activated as determined by an elevated ratio of associated guanosine triphosphate (GTP)/guanosine diphosphate (GDP), assayed by thin-layer chromatography of the nucleotides eluted from p21 RAS after immunoprecipitation with the Y13–259 antibody. Treatment of p210 bcr-abl-transformed cells with a specific tyrosine kinase inhibitor herbimycin A resulted in diminished tyrosine phosphorylation of p210 bcr-abl and associated proteins, without major reduction in expression of the p210 bcr-abl protein itself. Inhibition of p210 bcr-abl-dependent tyrosine phosphorylation resulted in a reduction of active p21RAS-GTP complexes in the transformed cells, in diminished expression of the nuclear early response genes c-jun and c-fos, and in lower cellular proliferation rate. To further implicate p21 RAS in these functional events downstream of p210 bcr-abl tyrosine phosphorylation, we targeted G- protein function directly by limiting the availability of GTP with the inosine monophosphate dehydrogenase inhibitor, tiazofurin (TR). In p210 bcr-abl-transformed cells treated for 4 hours with TR, in which the levels of GTP were reduced by 50%, but GDP, guanosine monophosphate, and adenosine triphosphate (ATP) were unaffected, p210 bcr-abl tyrosine phosphorylation was at control levels. However, expression of c-fos and c-jun nuclear proto-oncogenes were strongly inhibited and p21 RAS activity was downregulated. These findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS. Furthermore, p21 RAS activity is linked to pathways that regulate c-jun and c-fos expression.
4
Mandanas, RA, DS Leibowitz, K. Gharehbaghi, T. Tauchi, GS Burgess, K. Miyazawa, HN Jayaram e HS Boswell. "Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells". Blood 82, n. 6 (15 settembre 1993): 1838–47. http://dx.doi.org/10.1182/blood.v82.6.1838.bloodjournal8261838.
Testo completoAbstract (sommario):
The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth- factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence. In these p210 bcr-abl-transformed cells (H7 bcr-abl.A54) and in two other murine myeloid cell lines transformed to IL-3 independence by p210 bcr-abl, endogenous p21 RAS is activated as determined by an elevated ratio of associated guanosine triphosphate (GTP)/guanosine diphosphate (GDP), assayed by thin-layer chromatography of the nucleotides eluted from p21 RAS after immunoprecipitation with the Y13–259 antibody. Treatment of p210 bcr-abl-transformed cells with a specific tyrosine kinase inhibitor herbimycin A resulted in diminished tyrosine phosphorylation of p210 bcr-abl and associated proteins, without major reduction in expression of the p210 bcr-abl protein itself. Inhibition of p210 bcr-abl-dependent tyrosine phosphorylation resulted in a reduction of active p21RAS-GTP complexes in the transformed cells, in diminished expression of the nuclear early response genes c-jun and c-fos, and in lower cellular proliferation rate. To further implicate p21 RAS in these functional events downstream of p210 bcr-abl tyrosine phosphorylation, we targeted G- protein function directly by limiting the availability of GTP with the inosine monophosphate dehydrogenase inhibitor, tiazofurin (TR). In p210 bcr-abl-transformed cells treated for 4 hours with TR, in which the levels of GTP were reduced by 50%, but GDP, guanosine monophosphate, and adenosine triphosphate (ATP) were unaffected, p210 bcr-abl tyrosine phosphorylation was at control levels. However, expression of c-fos and c-jun nuclear proto-oncogenes were strongly inhibited and p21 RAS activity was downregulated. These findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS. Furthermore, p21 RAS activity is linked to pathways that regulate c-jun and c-fos expression.
5
Lacal, J. C., A. Cuadrado, J. E. Jones, R. Trotta, D. E. Burstein, T. Thomson e A. Pellicer. "Regulation of protein kinase C activity in neuronal differentiation induced by the N-ras oncogene in PC-12 cells". Molecular and Cellular Biology 10, n. 6 (giugno 1990): 2983–90. http://dx.doi.org/10.1128/mcb.10.6.2983-2990.1990.
Testo completoAbstract (sommario):
Expression of the N-ras oncogene under the control of the glucocorticoid-responsive promoter in the pheochromocytoma cell line UR61, a subline of PC-12 cells, has been used to investigate the differentiation process to neuronal cells triggered by ras oncogenes (I. Guerrero, A. Pellicer, and D. E. Burstein, Biochem. Biophys. Res. Commun. 150:1185-1192, 1988). Using ras-inducible cell lines, we observed that expression of the oncogenic N-ras p21 protein interferes with the ability of phorbol esters to induce downregulation of protein kinase C. This effect was associated with the appearance of immunologically detectable protein kinase C as well as the activity of the enzyme as analyzed either by binding of [3H]phorbol-12,13-dibutyrate in intact cells or by in vitro kinase activity. These results indicate a relationship between ras p21 and protein kinase C in neuronal differentiation in this model system. Comparison to the murine fibroblast system suggests that this relationship may be functional.
6
Lacal, J. C., A. Cuadrado, J. E. Jones, R. Trotta, D. E. Burstein, T. Thomson e A. Pellicer. "Regulation of protein kinase C activity in neuronal differentiation induced by the N-ras oncogene in PC-12 cells." Molecular and Cellular Biology 10, n. 6 (giugno 1990): 2983–90. http://dx.doi.org/10.1128/mcb.10.6.2983.
Testo completoAbstract (sommario):
Expression of the N-ras oncogene under the control of the glucocorticoid-responsive promoter in the pheochromocytoma cell line UR61, a subline of PC-12 cells, has been used to investigate the differentiation process to neuronal cells triggered by ras oncogenes (I. Guerrero, A. Pellicer, and D. E. Burstein, Biochem. Biophys. Res. Commun. 150:1185-1192, 1988). Using ras-inducible cell lines, we observed that expression of the oncogenic N-ras p21 protein interferes with the ability of phorbol esters to induce downregulation of protein kinase C. This effect was associated with the appearance of immunologically detectable protein kinase C as well as the activity of the enzyme as analyzed either by binding of [3H]phorbol-12,13-dibutyrate in intact cells or by in vitro kinase activity. These results indicate a relationship between ras p21 and protein kinase C in neuronal differentiation in this model system. Comparison to the murine fibroblast system suggests that this relationship may be functional.
7
Pan, B. T., e G. M. Cooper. "Role of phosphatidylinositide metabolism in ras-induced Xenopus oocyte maturation". Molecular and Cellular Biology 10, n. 3 (marzo 1990): 923–29. http://dx.doi.org/10.1128/mcb.10.3.923-929.1990.
Testo completoAbstract (sommario):
Microinjection of Xenopus oocytes with ras protein (p21) was used to investigate the role of phospholipid metabolism in ras-induced meiotic maturation. Induction of meiosis by ras was compared with induction by progesterone, insulin, and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Neomycin, which specifically binds to phosphatidylinositides and inhibits their metabolism, blocked meiotic maturation induced by ras or insulin but not by progesterone or TPA. In addition, p21 and TPA, but not insulin or progesterone, stimulated the incorporation of 32Pi into oocyte lipids. ras protein specifically stimulated 32P incorporation into phosphatidylinositides, whereas both ras and TPA stimulated 32P incorporation into phosphatidylcholine and phosphatidylethanolamine. The stimulatory effect of p21 on phosphatidylinositide metabolism correlated with the dose response and kinetics of ras-induced meiotic maturation. In addition, the ras oncogene protein was more potent than the proto-oncogene protein both in inducing meiotic maturation and in stimulating phosphatidylinositide metabolism. These results indicate that phosphatidylinositide turnover is required for ras-induced meiosis and suggest that phosphatidylinositide-derived second messengers mediate the biological activity of ras in Xenopus oocytes.
8
Pan, B. T., e G. M. Cooper. "Role of phosphatidylinositide metabolism in ras-induced Xenopus oocyte maturation." Molecular and Cellular Biology 10, n. 3 (marzo 1990): 923–29. http://dx.doi.org/10.1128/mcb.10.3.923.
Testo completoAbstract (sommario):
Microinjection of Xenopus oocytes with ras protein (p21) was used to investigate the role of phospholipid metabolism in ras-induced meiotic maturation. Induction of meiosis by ras was compared with induction by progesterone, insulin, and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Neomycin, which specifically binds to phosphatidylinositides and inhibits their metabolism, blocked meiotic maturation induced by ras or insulin but not by progesterone or TPA. In addition, p21 and TPA, but not insulin or progesterone, stimulated the incorporation of 32Pi into oocyte lipids. ras protein specifically stimulated 32P incorporation into phosphatidylinositides, whereas both ras and TPA stimulated 32P incorporation into phosphatidylcholine and phosphatidylethanolamine. The stimulatory effect of p21 on phosphatidylinositide metabolism correlated with the dose response and kinetics of ras-induced meiotic maturation. In addition, the ras oncogene protein was more potent than the proto-oncogene protein both in inducing meiotic maturation and in stimulating phosphatidylinositide metabolism. These results indicate that phosphatidylinositide turnover is required for ras-induced meiosis and suggest that phosphatidylinositide-derived second messengers mediate the biological activity of ras in Xenopus oocytes.
9
McCoy, M. S., e R. A. Weinberg. "A human Ki-ras oncogene encodes two transforming p21 proteins". Molecular and Cellular Biology 6, n. 4 (aprile 1986): 1326–28. http://dx.doi.org/10.1128/mcb.6.4.1326-1328.1986.
Testo completoAbstract (sommario):
The human Ki-ras gene was previously reported to contain two alternative fourth exons which encode two distinct p21 proteins differing only at their carboxy termini. The present study shows that either p21 protein is able on its own to transform NIH 3T3 cells to a tumorigenic state.
10
McCoy, M. S., e R. A. Weinberg. "A human Ki-ras oncogene encodes two transforming p21 proteins." Molecular and Cellular Biology 6, n. 4 (aprile 1986): 1326–28. http://dx.doi.org/10.1128/mcb.6.4.1326.
Testo completoAbstract (sommario):
The human Ki-ras gene was previously reported to contain two alternative fourth exons which encode two distinct p21 proteins differing only at their carboxy termini. The present study shows that either p21 protein is able on its own to transform NIH 3T3 cells to a tumorigenic state.
Tesi sul tema "Oncogene Protein p21(ras)"
1
Iritani, Brian Masao. "Control of B lymphocyte development by Ras and Raf /". Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/8322.
Testo completo
2
Bradbury, Andrew W. "Cyclic AMP binding proteins and ras p21 oncogene expression in human colorectal cancer and mucosa". Thesis, University of Edinburgh, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531024.
Testo completo
3
Estrozi, Bruna. "Avaliação anatomoclínica e molecular do melanoma cutâneo em pacientes jovens (idade 18-30 anos)". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-01042015-144721/.
Testo completoAbstract (sommario):
A incidência do melanoma cutâneo em pacientes adultos jovens tem aumentado consideravelmente nos últimos anos. Há, contudo, carência de conhecimentos clinicopatológicos e moleculares sobre os melanomas que ocorrem nessa faixa etária. O presente estudo teve por objetivo avaliar 132 casos de melanoma cutâneo primário em pacientes com idade entre 18 e 30 anos, com ênfase no estudo das características clínicas, histopatológicas e avaliação molecular das mutações nos genes BRAF, NRAS e KIT. Em relação aos achados clínicos e histopatológicos, houve predomínio de indivíduos do sexo feminino (61,4%), sendo o tronco o sítio anatômico mais comumente envolvido (44,3%) e o melanoma extensivo superficial o tipo histológico predominante (79,5%). A mutação V600E no gene BRAF (BRAFV600E) foi analisada em 93 casos, utilizando-se a técnica de RT-PCR. Essa mutação foi identificada em 38,7% (36/93) e, estatisticamente, associada à fase vertical de crescimento (p = 0,01), infiltrado inflamatório discreto (p = 0,02) e presença de mitose intradérmica (p = 0,004). Houve, ainda, forte indício de associação com a presença de ulceração (p = 0,05). Todas essas variáveis apresentaram associação com pior prognóstico do melanoma cutâneo. Observou-se predomínio da mutação BRAFV600E em regiões anatômicas relacionadas à exposição solar intermitente. Nenhum caso de melanoma com fenômeno de regressão apresentou mutação BRAFV600E (p < 0,05). Não houve associação significativa entre BRAFV600E e sexo, tipo histológico, nível de Clark, índice de Breslow, elastose solar, invasão angiolinfática e perineural, satelitose, nevo melanocítico coexistente e sobrevida. A pesquisa de mutações NRAS, pela técnica de RT-PCR, detectou frequência de 3,95% (3/76). As três mutações encontradas foram do tipo 61K e ocorreram em pacientes do sexo masculino e em região de cabeça e pescoço. As mutações BRAFV600E e NRAS, quando presentes, eram mutuamente exclusivas. A frequência de mutações KIT, analisadas por sequenciamento, foi de 11,1% (3/27). As três mutações identificadas estavam localizadas no éxon 9 (G510, G498S e 489I). Houve concomitância de casos com mutação KIT tanto com NRAS, como com BRAFV600E. Devido ao pequeno número de casos com mutação em KIT e NRAS, não foi possível estabelecer correlações clínicas e histopatológicas com esses genes. Este estudo é o primeiro a descrever as mutações G510D e G498S no gene KIT em melanomas cutâneos. No presente estudo, a mutação BRAFV600E, em melanomas cutâneos de adultos jovens, correlacionou-se com características anatomoclínicas de pior prognóstico em relação aos melanomas selvagens para BRAFV600EThe incidence of cutaneous melanoma in young adults has dramatically increased in recent years. However, there is scarce data about the clinicopathological and molecular characteristics on the melanomas occurring at this age group. The present study aimed to evaluate 132 patients aged between 18 and 30 years with primary cutaneous melanoma with emphasis on the study of clinical, histopathological characteristics and molecular evaluation of mutations in BRAF, NRAS and KIT genes. Regarding the clinical and histopathological findings, the following results were found: female predominance (61.4%), trunk was the most commonly anatomical site involved (44.3%) and superficial spreading melanoma, was the most common histological type (79.5 %). The V600E mutation in BRAF (BRAFV600E) gene was analyzed in 93 cases, using RT-PCR. It was present in 38.7% (36/93) and statistically related to the vertical growth phase (p = 0.01), mild inflammatory infiltration (p = 0.02) and the presence of intradermal mitosis (p = 0.004). There was, also, strongly evidence of an association with the presence of ulceration (p = 0.05). Worse prognosis was associated with these variables. There was a predominance of BRAFV600E mutation in anatomical regions related to intermittent sun exposure. No cases of melanoma with BRAFV600E mutation showed regression phenomenon (p < 0.05). There was no significant association between BRAFV600E and gender, histological type, Clark level, Breslow thickness, solar elastosis, angiolymphatic and perineural invasion, sattelitosis, coexisting melanocytic nevus and survival. The presence of a mutation in NRAS, by RT-PCR was seen in 3.95% (3/76) of the cases. All these three mutations were of type 61K, occurred in male patients and the head and neck region. BRAFV600E and NRAS mutations, when present, were mutually exclusive. The frequency of KIT mutations, analyzed by sequencing, was 11.1% (3/27). The three mutations identified in this gene were located in exon 9 (G510, G498S and 489I). Concomitant mutations were found between KIT and NRAS and BRAFV600E. Due to the small number of KIT and NRAS mutated cases, it was not possible to establish clinical and histopathological correlations and mutation status in these genes. This study was the first to describe the G510D and G498S mutations in KIT gene in cutaneous melanomas. In the present study, BRAFV600E mutation in cutaneous melanoma of young adults correlated with anatomic and clinical features of worse prognosis compared to wild type
4
Filho, João Bosco de Oliveira. "Mutação em NRAS causa uma síndrome autoimune linfoproliferativa humana". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-04112008-174252/.
Testo completoAbstract (sommario):
A subfamília p21 RAS de pequenas GTPases, incluindo KRAS, HRAS e NRAS, participa de muitas redes de sinalização, incluindo proliferação celular, organização do citoesqueleto e apoptose, e é o alvo mais freqüente de mutações ativadoras em câncer. Mutações germinativas em KRAS e HRAS causam graves anormalidades desenvolvimentais levando às síndromes de Noonan, cárdio-facial-cutânea e Costello, porem mutações ativadoras germinativas em NRAS não foram descritas até hoje. A síndrome autoimune linfoproliferativa (ALPS) é o mais comum defeito genético de apoptose linfocitária, cursando com autoimunidade e acúmulo excessivo de linfócitos, particularmente do tipo T + CD4- CD8-. As mutações causadoras de ALPS descritas até hoje afetam a apoptose mediada por Fas, uma das vias extrínsecas de apoptose. Nós demonstramos aqui que os principais achados clínicos de ALPS, bem como uma predisposição para tumores hematológicos, podem ser causados por uma mutação heterozigota ativadora G13D no oncogene NRAS, sem causar prejuízo na apoptose mediada por Fas. O aumento na quantidade intracelular de NRAS ativo, ligado a GTP, induziu a um aumento da sinalização na via RAF/MEK/ERK, o que suprimiu a expressão da proteína pró-apoptótica BIM, e atenuou a apoptose intrínseca mitocondrial. Desta forma, uma mutação germinativa ativadora em NRAS causou um fenótipo clinico diferente do visto em pacientes com mutações em outros membros da família p21 RAS, cursando com um defeito imunológico seletivo, sem distúrbios generalizados do desenvolvimentoThe p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4-, CD8- ab T cells. Mutations in ALPS typically affect Fas-mediated apoptosis, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair Fas-mediated apoptosis. The increase in active, GTP-bound NRAS augmented RAF/MEK/ERK signaling which markedly decreased the pro-apoptotic protein BIM and attenuated intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects
5
Driscoll, David R. "The Impact of mTORC2 Signaling on the Initiation and Progression of KRAS-Driven Pancreatic Neoplasias: A Dissertation". eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/821.
Testo completoAbstract (sommario):
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, develops through progression of premalignant pancreatic intraepithelial neoplasias (PanINs). In mouse-models, KRAS-activation in acinar cells induced an acinar-to-ductal metaplasia (ADM), and mutation of the Kras oncogene is believed to initiate PanIN formation. ADM is also promoted by pancreatic injury, which cooperates with activated KRAS to stimulate PanIN and PDAC formation from metaplastic ducts.
Our lab, and others, have shown that the downstream PI3K/AKT pathway is important for KRAS-mediated proliferation and survival in vitro and in vivo. Prior studies have demonstrated that full activation of AKT requires both PDK1- mediated phosphorylation of AKTT308 and mTOR complex 2 (mTORC2)-mediated phosphorylation of AKTS473. Given the importance of the PI3K/AKT signaling axis, I hypothesized that mTORC2 is required for KRAS-driven pancreatic tumorigenesis and investigated this relationship in mice by combining pancreasspecific expression of an activated KRASG12D molecule with deletion of the essential mTORC2 subunit RICTOR.
In the context of activated KRAS, Rictor-null pancreata developed fewer PanIN lesions; these lesions lacked mTORC2 signaling and their proliferation and progression were impaired. Higher levels of nuclear cyclin dependent kinase inhibitors (CDKIs) were maintained in Rictor-null lesions, and nuclear BMI1, a known regulator of the CDKI Cdkn2a, inversely correlated with their expression.Rictor was not required for KRAS-driven ADM following acute pancreatitis, however the inverse correlation between CDKIs and BMI1 was maintained in this system. Treatment of PDX-Cre;KRASG12D/+;Trp53R172H/+ mice with an mTORC1/2 inhibitor delayed tumor formation, and prolonged the survival of mice with late stage PDAC. Knockdown of Rictor in established PDAC cell lines impaired proliferation and anchorage independent growth supporting a role for mTORC2 in fully transformed cells.
These data suggest that mTORC2 cooperates with activated KRAS in the initiation and progression of PanIN lesions and is required for the transformation and maintenance of PDAC. My work illustrates phenotypic differences between pancreatic loss of Rictor and PDK1 in the context of KRAS, broadens our understanding of this signaling node and suggests that mTORC2 may potentially be a viable target for PDAC therapies.
6
Driscoll, David R. "The Impact of mTORC2 Signaling on the Initiation and Progression of KRAS-Driven Pancreatic Neoplasias: A Dissertation". eScholarship@UMMS, 2003. http://escholarship.umassmed.edu/gsbs_diss/821.
Testo completoAbstract (sommario):
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, develops through progression of premalignant pancreatic intraepithelial neoplasias (PanINs). In mouse-models, KRAS-activation in acinar cells induced an acinar-to-ductal metaplasia (ADM), and mutation of the Kras oncogene is believed to initiate PanIN formation. ADM is also promoted by pancreatic injury, which cooperates with activated KRAS to stimulate PanIN and PDAC formation from metaplastic ducts.
Our lab, and others, have shown that the downstream PI3K/AKT pathway is important for KRAS-mediated proliferation and survival in vitro and in vivo. Prior studies have demonstrated that full activation of AKT requires both PDK1- mediated phosphorylation of AKTT308 and mTOR complex 2 (mTORC2)-mediated phosphorylation of AKTS473. Given the importance of the PI3K/AKT signaling axis, I hypothesized that mTORC2 is required for KRAS-driven pancreatic tumorigenesis and investigated this relationship in mice by combining pancreasspecific expression of an activated KRASG12D molecule with deletion of the essential mTORC2 subunit RICTOR.
In the context of activated KRAS, Rictor-null pancreata developed fewer PanIN lesions; these lesions lacked mTORC2 signaling and their proliferation and progression were impaired. Higher levels of nuclear cyclin dependent kinase inhibitors (CDKIs) were maintained in Rictor-null lesions, and nuclear BMI1, a known regulator of the CDKI Cdkn2a, inversely correlated with their expression.Rictor was not required for KRAS-driven ADM following acute pancreatitis, however the inverse correlation between CDKIs and BMI1 was maintained in this system. Treatment of PDX-Cre;KRASG12D/+;Trp53R172H/+ mice with an mTORC1/2 inhibitor delayed tumor formation, and prolonged the survival of mice with late stage PDAC. Knockdown of Rictor in established PDAC cell lines impaired proliferation and anchorage independent growth supporting a role for mTORC2 in fully transformed cells.
These data suggest that mTORC2 cooperates with activated KRAS in the initiation and progression of PanIN lesions and is required for the transformation and maintenance of PDAC. My work illustrates phenotypic differences between pancreatic loss of Rictor and PDK1 in the context of KRAS, broadens our understanding of this signaling node and suggests that mTORC2 may potentially be a viable target for PDAC therapies.
7
Martins, Carla Pedro. "Cip/Kip proteins in the suppression of murine lymphomagenesis". [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/67628.
Testo completo
8
Alexandre, Cristianne da Silva. "As células linhagem negativa (Lin) de medula óssea atenuam a progressão da doença renal crônica". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5148/tde-10032008-150329/.
Testo completoAbstract (sommario):
Introdução: A doença renal crônica continua sendo um desafio no campo da pesquisa médica. Atualmente um interesse crescente tem surgido no intuito de avaliar o potencial de células tronco em retardar o avanço de doenças crônicas progressivas. Material e Métodos: Para determinar o efeito dessas células em um modelo de progressão de doença renal crônica foram usadas células linhagem negativa (Lin ) separadas magneticamente e injetadas em ratos submetidos à injúria renal. Ratos singênicos Fischer 344 foram submetidos à nefrectomia 5/6 (Nx) e divididos em 3 grupos: Nx (não tratados); NxSC1 (submetidos à infusão de 2 106 células Lin no 15º dia de pós-operatório); e NxSC3 (submetidos à infusão de 2 106 células Lin no 15º, 30º e 45º dias de pós-operatório). No 60º dia de pós-operatório clearance de inulina, imunohistoquímica e immunoblotting foram realizados. Resultados: Os animais submetidos à nefrectomia apresentaram redução do clearance de inulina (0,33 ± 0,02 ml/min/100g peso corpóreo), proteinúria (12 ± 0,5 mg/24hs) , anemia e hipertensão (145 ± 7,7 mmHg) compatíveis com doença renal crônica. A infusão de células Lin- resultou em atenuação da proteinúria (p<0,05) com relação aos animais não tratados a despeito de não ter havido diferença nos níveis de pressão arterial e aldosterona plasmática. Esses achados foram similares entre os grupos tratados com uma ou com três infusões de células. Adicionalmente a infusão de células resultou em redução do índice de glomeruloesclerose e da área intersticial relativa (p<0,05), menor infiltração do tecido renal por macrófagos e linfócitos e menor proliferação celular. A expressão tecidual do p21 e de VEGF já foi associada à aceleração da progressão da lesão renal crônica. No nosso modelo ambas as proteínas tiveram sua expressão reduzida. A redução da expressão tecidual de eNOS tem sido implicada na progressão da doença renal. Em nosso modelo houve aumento dessa expressão após infusão das células Conclusões: A infusão de células Linatenuou todos os marcadores de injúria renal em um modelo de doença precoce possivelmente através de um mecanismo imunomodulador.Progressive renal failure continues to be a challenge. The use of bone marrowderived stem cells (SCs) represents a means of meeting that challenge. We used lineage-negative (Lin-) SCs to test the hypothesis that Lin- cell infusion decreases renal injury. Syngeneic Fischer 344 rats were submitted to 5/6 nephrectomy and divided into 3 groups: Nx (untreated); NxSC1 (receiving 2 × 106 Lin- cells on postnephrectomy day 15); and NxSC3 (receiving 2 × 106 Lin- cells on postnephrectomy days 15, 30 and 45). Controls were unoperated/untreated. On postnephrectomy day 60, clearance studies, immunohistochemistry and immunoblotting were performed. Lin- cell infusion effectively reduced postnephrectomy proteinuria, glomerulosclerosis, anemia, renal infiltration of immune cells and monocyte chemoattractant protein-1 protein expression, as well as decreasing the interstitial area. Immunostaining for proliferating cell nuclear antigen showed that, in comparison with controls, Nx rats presented greater cell proliferation, whereas NxSC1 rats and NxSC3 rats presented less cell proliferation than did Nx rats. Protein expression of p21 and VEGF increased after nephrectomy and decreased after Lin- cell infusion. Protein expression of eNOS reduced after nephrectomy and increased after cell infusion. These data suggest that SC treatment ameliorates progressive end-stage renal disease.
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Golbert, Lenara. "Implicações do aumento da expressão do proto-oncogene Ras no bócio multinodular". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2006. http://hdl.handle.net/10183/7815.
Testo completoAbstract (sommario):
O bócio multinodular (BMN) é definido como aumento da glândula tireóide devido a proliferação de tireócitos e caracteriza-se pela heterogeneidade no crescimento e função das células foliculares. É uma patologia comum, com aumento da prevalência em áreas com deficiência de iodo, sendo este o principal fator etiológico do BMN. O BMN é considerado uma neoplasia benigna da tireóide. A patogênese desta disfunção ainda não foi inteiramente elucidada. Nesta revisão serão abordados os mecanismos envolvidos na patogênese e os principais aspectos etiológicos e clínicos do BMN.Multinodular goiter (MNG) is an enlargement of the thyroid gland and is characterized by heterogeneity in growth and function of thyroid follicular cells. It is a common pathology, with higher prevalence in iodine deficiency areas. Iodine deficiency is the main etiologic factor for MNG. MNG have been considered a true thyroid neoplasm. The pathogenesis of multinodular goiter is not yet clarified. The purpose of this review is to summarize the current knowledge of MNG with respect to the pathology, etiologic and clinical characteristics.
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Benisty, Hannah 1986. "Post-transcriptional determinants of RAS protein abundance". Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/668206.
Testo completoAbstract (sommario):
The RAS oncogenes KRAS, NRAS and HRAS are mutated in one third of human cancers where they exhibit different mutation patterns. A potential factor contributing to this mutation bias is the variation of RAS expression levels. Here, I investigate some of the determinants of RAS protein abundance. First, I examine whether codon bias among RAS genes and within other cancer gene families plays a role in cell context-specific expression. I further describe a tRNA expression program that favors oncogene translation in proliferating cells. Second, I investigate why oncogenic RAS mutants exhibit a higher protein abundance than the RAS wild type. In this context, I study the underlying mechanisms leading to this variation and more specifically how protein-protein interactions between RAS and its downstream binding partners change the protein turnover of RAS and therefore, its protein abundance. Overall, this thesis provides insight into the possible relevance of RAS protein synthesis and protein degradation as determinants of RAS mutation patterns in human cancers.Els oncogens KRAS, NRAS i HRAS estan mutats en un terç dels càncers en humans on hi exhibeixen patrons de mutació diferents. Un possible factor que contribueix a aquest biaix de mutació és la variació dels nivells d'expressió de RAS. En aquesta tesi investigo els elements determinants de l'abundància de la proteïna RAS. Primer, examino si el biaix de codó entre els gens RAS i entre gens d'altres famílies implicades en càncer contribueix a les diferències d'expressió, en funció del context cel·lular. Així mateix, descric un programa d'expressió de tRNA que facilita la traducció d'oncogens en cèl·lules proliferatives. En segon lloc, investigo per què mutants oncogènics de RAS tenen una abundància de proteïna més elevada que la RAS salvatge. Així mateix, estudio els mecanismes subjacents responsables d'aquesta variació i més concretament el paper de les interaccions de RAS amb altres proteïnes en la regulació de la seva abundància. Així doncs, aquesta tesi estudia la possible rellevància dels mecanismes de síntesi i degradació de la proteïna RAS en els patrons de mutació en càncer.
Libri sul tema "Oncogene Protein p21(ras)"
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Vivo, Immaculata De. Mutated ras P21 in chemical carcinogenesis of vinyl chloride-exposed workers. 1993, 1993.
Cerca il testo completoCapitoli di libri sul tema "Oncogene Protein p21(ras)"
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Yiagnisis, M., K. Papadimitriou e D. A. Spandidos. "Human Thyroid Neoplasms Express ras p21 Protein at High Levels". In ras Oncogenes, 47–49. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-1235-3_8.
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de Gunzburg, Jean, Rebecca Riehl e Robert A. Weinberg. "Identification of a Protein Interacting with ras-p21- by Chemical Cross-Linking". In ras Oncogenes, 281–85. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-1235-3_37.
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Willumsen, Berthe M., e Douglas R. Lowy. "P21 ras Transforming Protein: Significance of the Carboxy Terminus". In RNA Tumor Viruses, Oncogenes, Human Cancer and AIDS: On the Frontiers of Understanding, 25–40. Boston, MA: Springer US, 1985. http://dx.doi.org/10.1007/978-1-4613-2583-3_3.
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Pizon, V., P. Chardin, I. Lerosey e A. Tavitian. "The rap Proteins : GTP Binding Proteins Related to p21 ras with a Possible Reversion Effect on ras Transformed Cells". In ras Oncogenes, 83–91. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-1235-3_13.
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Marshall, M. S., M. D. Schaber, U. S. Vogel, W. S. Hill, A. S. Ng, E. M. Scolnick, R. A. F. Dixon, I. S. Sigal e J. B. Gibbs. "The ras Oncogene Protein". In Molecular Mechanisms of Hormone Action, 85–91. Berlin, Heidelberg: Springer Berlin Heidelberg, 1989. http://dx.doi.org/10.1007/978-3-642-75022-9_10.
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Leftheris, K., T. Kline, W. Lau, L. Mueller, V. S. Goodfellow, M. K. DeVirgilio, Y. H. Cho et al. "Tetrapeptide based inhibitors of p21 ras protein farnesyl transferase". In Peptides, 622–24. Dordrecht: Springer Netherlands, 1994. http://dx.doi.org/10.1007/978-94-011-0683-2_205.
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Teruya, Kiichiro, Sanetaka Shirahata, Takahiro Yano, Junko Watanabe, Kiyohiko ki Se, Kazuhiro Osada, Hirofumi Tachibana, Hideya Ohashi e Hiroki Murakami. "RAS Oncogene Enhances the Various Recombinant Protein Productivities of BHK-21 Cells Regulated by the CMV Promoter". In Animal Cell Technology: Developments Towards the 21st Century, 91–95. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-011-0437-1_15.
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Agnantis, N. J., A. Pintzas, A. Kakkanas, P. Markoulatos e D. A. Spandidos. "Expression of the ras Oncogene p 21 Protein in Human Breast Tumors and in Several Benign Conditions Using the Y13 259 Monoclonal Antibody". In Fundamental Problems in Breast Cancer, 323–25. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4613-2049-4_36.
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Donato, Armando Di, Shiv K. Srivastava e Juan Carlos Lacal. "Analysis of the Biochemical and Biological Activities of Deletion Mutants of the H-Ras P21 Protein Suggest That Gap is an Essential Component of Its Effector Function". In The Guanine — Nucleotide Binding Proteins, 179–90. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-2037-2_17.
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Wittinghofer, Alfred, e Alfonso Valencia. "Three-dimensional structure of Ras and Ras-related proteins". In Guidebook to the Sinall GTPases, 20–29. Oxford University PressOxford, 1995. http://dx.doi.org/10.1093/oso/9780198599456.003.0003.
Testo completoAbstract (sommario):
Abstract The structures of several different wild-type and mutantp21 complexes have been determined by two groups. A listof the published structures is shown in Table 1 togetherwith the resolutions obtained in the crystallographic analyses.For wild-type and one oncogenic mutant both thetriphosphate and diphosphate structures have been determined.For the triphosphate complex of p21 the non-cleavableanalogues GppNHp and Gpp(CH2)p were used,because GTP and even GTPy.i are hydrolysed by p21 duringcrystallization.
Atti di convegni sul tema "Oncogene Protein p21(ras)"
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Pirogova, Elena, Vuk Vojisavljevic e Irena Cosic. "Prediction of protein active and/or binding site using time-frequency analysis: Application to ras oncogene proteins". In 2012 ISSNIP Biosignals and Biorobotics Conference: Biosignals and Robotics for Better and Safer Living (BRC). IEEE, 2012. http://dx.doi.org/10.1109/brc.2012.6222173.
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