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Müer, Annika [Verfasser]. "Funktionelle Charakterisierung des p14ARF-Tumorsuppressorsignalwegs / Annika Müer". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1029792585/34.
Pełny tekst źródłaAbraham, Aswin George. "Nucleophosmin and p14ARF mediated regulation of p53". Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:06e101f9-f0e3-42b9-ada9-7a1b1a1f4a87.
Pełny tekst źródłaLindström, Mikael. "Functional characterization of the alternative reading frame protein p14ARF /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-917-x.
Pełny tekst źródłaCarr-Wilkinson, Jane. "Inactivation of the p53/MDM2/p14ARF pathway in neuroblastoma". Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.515033.
Pełny tekst źródłaMistry, Sushilaben Harkisandas. "The role of p14ARF in familial and sporadic melanoma". Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413193.
Pełny tekst źródłaDayde, Delphine. "Liens fonctionnels entre l'EGFR et P14ARF : contribution à la carcinogenèse pulmonaire". Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV071/document.
Pełny tekst źródłaEGFR is a transmembrane tyrosine kinase (TK) receptor which activates proliferative and survival signals. In lung cancer, its activity is frequently deregulated by overexpression and/or mutation in its TK domain. These mutations are mainly of two types (L858R and Del19) and are called « driver mutations » because they induce constitutive activation of EGFR oncogenic signaling. They also represent a predictive responsive factor to EGFR TKIs that specifically inhibit this receptor. P14ARF is a tumor suppressor that restricts cellular proliferation and maintains genomic stability. We described its inactivation in lung cancer and demonstrated that its expression inhibits their development. Our recent results show that the expression of p14ARF is inhibited in a majority of lung adenocarcinomas expressing an activating EGFR mutation. Based on these results we hypothesized that inhibition of p14ARF expression contributes to clonal expansion of mutated EGFR-bearing tumor. P14ARF could be a break to EGFR oncogenic activity.In different models of lung adenocarcinoma expressing a L858R EGFR mutant we show that transient expression of p14ARF activates a pro-apoptotic STAT3/Bcl-2-dependent signaling pathway. In turn, EGFR inhibits the expression of p14ARF and blocks its pro-apoptotic function. We also show that EGFR (wild type or mutated) activation inhibits the expression of p14ARF at the transcriptional level. This implies a nuclear translocation of EGFR controlled by Class III PI3K (Vps34) and its fixation to the ARF promoter. This work identifies for the first time a functional link between EGFR and p14ARF signaling pathways. They highlight a new mechanism of tumor progression by which a nuclear EGFR signaling inactivates the tumor suppressor p14ARF to allow tumor growth
Gallagher, Stuart John. "The Role of the p14ARF Tumour Suppressor in Promoting Apoptosis". Thesis, The University of Sydney, 2008. http://hdl.handle.net/2123/3597.
Pełny tekst źródłaGallagher, Stuart John. "The Role of the p14ARF Tumour Suppressor in Promoting Apoptosis". University of Sydney, 2008. http://hdl.handle.net/2123/3597.
Pełny tekst źródłaThe incidence of melanoma has risen dramatically during the past three decades, yet there has been little improvement in effective treatments for this intractable and aggressive disease. Melanoma tumours are notoriously resistant to apoptosis, a cell suicide program that is activated by most cancer therapies. This thesis explores the role of the melanoma susceptibility gene product p14ARF in promoting cell cycle arrest and apoptosis, in order to resolve the impact of this tumour suppressor in melanomagenesis and melanoma susceptibility. The p14ARF tumour suppressor gene is mutated in almost half of all cancers, and germline mutations in p14ARF confer a greatly increased risk of developing melanoma. The primary function of p14ARF is to relay oncogenic signals to p53, a central regulator of cellular response to stress. There is conflicting evidence regarding the role of p14ARF in promoting apoptosis. Much of the current evidence is based on murine studies, which may not translate accurately to humans due to important differences in animal physiology and the primary sequence and functions of the mouse and human ARF proteins. Furthermore, results from previous studies are often compounded by supra-physiological expression of p14ARF, and are complicated by the fact that p14ARF shares its genomic sequence with the p16INK4a tumour suppressor gene. This study demonstrates that p14ARF expression in human cancer and primary cell lines promotes rapid p53-dependent cell cycle arrest, rather than apoptosis. As p14ARF expression did not induce apoptosis, we investigated if p14ARF could modulate the sensitivity of a cell to apoptosis induced by cytotoxic agents. Using a p14ARF-inducible U2OS osteosarcoma cell line model, we examined the impact of p14ARF expression on the apoptotic response of the cell to a panel of thirteen cytotoxic agents. p14ARF expression increased apoptosis caused by a sub-set of agents, including trichostatin A, sodium butyrate, DRB, Adriamycin and UVB radiation. p14ARF-mediated chemosensitivity was p53- and caspase-dependent, and involved the loss of mitochondrial potential. While loss of mitochondrial potential was dependent on p53, it was not blocked by caspase inhibition, demonstrating that caspases play a role downstream of mitochondrial depolarisation. Inhibition of individual components of the apoptotic program showed that p14ARF-mediated chemosensitivity was not strictly dependent on the pro-apoptotic Bax or Fas proteins. We also investigated whether p14ARF could sensitise melanoma to chemotherapeutics in vivo. We investigated the expression level of p14ARF, p16INK4a and MITFm and mutation status of B-RAF, N-RAS and PTEN in melanomas from 30 patients that had undergone isolated limb infusion - a palliative therapeutic strategy that results in much higher response rates than systemic treatment. Expression of p14ARF did not predict response to the drugs actinomycin D and melphalan . Instead, high expression of p16INK4a and presence of activating N-RAS mutation were independent predictors of response to high doses of these chemotherapeutic drugs. This work suggests that p14ARF analogues may be beneficial adjuncts in cancer therapy, but are unlikely to be effective as single agents. Additionally, p14ARF mimetics will only be effective in tumours with intact p53 signalling. Melanomas frequently carry functional p53, and may be susceptible to this mode of treatment providing the apoptotic pathway downstream of p53 is intact or can be restored.
Andrique, Laetitia. "Nouveaux partenaires du suppresseur de tumeurs p14ARF : découverte de nouvelles fonctions indépendantes de p53". Poitiers, 2007. http://www.theses.fr/2007POIT1403.
Pełny tekst źródłaStraza, Michael W. "A Tale of Two ARFs: Tumor Suppressor and Anti-viral Functions of p14ARF: A Dissertation". eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/472.
Pełny tekst źródłaGamble, Laura Dawn. "MYCN and the p53-MDM2/MDMX-p14ARF network in neuroblastoma amd response to MDM2-p53 antagonists". Thesis, University of Newcastle upon Tyne, 2012. http://hdl.handle.net/10443/1350.
Pełny tekst źródłaMilojkovic, Ana [Verfasser]. "The tumour suppressor protein p14ARF regulates cell cycle checkpoint control and induces cell death / Ana Milojkovic". Berlin : Freie Universität Berlin, 2010. http://d-nb.info/1024744140/34.
Pełny tekst źródłaJunqueira, Mara de Souza. "Caracterização das vias de transformação maligna de uma nova linhagem estabelecida de melanoma murino". Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-20092010-183837/.
Pełny tekst źródłaA novel murine melanoma cell line named Mgal3 was generated from embryo explants. This cell line gave rise to metastatic tumors when injected subcutaneously in C57bl/6 mice. Tumor histogenesis was determined at the cytochemical (Fontana Masson staining), immunohistochemical (staining with anti-HMB45 and anti-S100) and ultrastructural levels. Mgal3 produces high amounts of retroviral C particles and was recognized by the mAb MM2-9B6, which reacts with a melanoma associated antigen derived from the envelope of the ecotropic retrovirus MelArv. No mutations were found in TP53 exons 5-8, however loss of CDKN2a expression was observed. Treatment of Mgal3 with the demethylating agent azadeoxycytidine indicated that at least one of the genes encoded at the CDKN2a locus was silenced by promoter hypermethylation. Furthermore, this cell line did not express the animal lectin, galectin-3. The galectin-3 gene promoter seemed to be hypermethylated, since treatment of Mgal3 with azadeoxycytidine led to the de novo expression of the lectin.
Mendonça, Samir Andrade. "Desenvolvimento e investigação da transferência gênica de p14ARF e interferon-beta em linhagens celulares de melanoma humano". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-07022019-093142/.
Pełny tekst źródłaMelanoma is one of the types of skin cancer whose frequency has grown in the last years and presents a high mortality rate, despite its low prevalence. Although there has been considerable progress in therapeutic proposals in recent years, it is still necessary to develop new approaches, being gene therapy a promising possibility for this. With the use of adenoviral vectors with a p53 responsive promoter (PGTx beta) for the gene transfer of p19Arf (tumor suppressor protein) and interferon-beta (immunomodulatory cytokine) in murine melanoma cells bearing wild-type Trp53 gene, our group previously demonstrated that the combination of the two genes, but not individual treatment, promotes a synergistic cytotoxic effect with the release of immunogenic death markers in vitro; and significant reduction of tumor progression with a strong immune response mediated by CD4+ and CD8+ T lymphocytes, NK cells and neutrophils in tumor challenges in vivo. However, as the translation for human melanoma models was still at an early stage, it still was not possible to confirm whether these benefits would also be recapitulated in a human model. Initial observations suggested that interferon-beta gene transfer is sufficient to induce cell death in wild-type TP53-bearing human melanoma cell lines, with the effect of p14ARF gene transfer and the role for endogenous p53 in this response yet to be investigated. Thus, the present work aimed to evaluate the antitumor effects induced upon the combined gene transfer of p14ARF and interferon-beta in human melanoma cell lines with and without a functional p53 pathway. For this, different cell lines bearing wild-type TP53 or with different mutations were used and adenoviral vectors with the constitutive CMV promoter were also constructed, making possible the expression of the transgenes independently of the endogenous TP53 status. The present work showed that the combined transfer of interferon-beta and p14ARF was advantageous in cytotoxic stimulation and negative regulation in population dynamics for both cell lines UACC-62 and SK-Mel-29, regardless of p53 pathway status. In the evaluation of the triggered cell death mechanisms it was observed that both cell lines presented positive markers of the apoptosis pathway, but with possible participation of other cell death mechanism, such as necrosis, for the mutated TP53 cell line SK-Mel-29. In addition, we showed that the treatments potentially induced cell death pathways with immunogenic features including the secretion of ATP and calreticulin exposure, being the latter marker more significantly presented after the combined treatment. Thus, we recapitulated the benefit observed in murine model for the gene transfer of interferon-beta and p14ARF in the model of human melanoma, and investigated important markers for the translation of the melanoma therapeutic proposal
Muniz, Viviane Palhares. "The role of Parf, a novel partner of ARF, in pancreatic ductal adenocarcinoma and in ARF signaling". Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3503.
Pełny tekst źródłaVENEZIANO, Lorena. "MECHANISMS OF CHROMOSOMAL INSTABILITY: RELATIONSHIP BETWEEN TUMOR SUPPRESSORS AND SAC GENES". Doctoral thesis, Università degli Studi di Palermo, 2017. http://hdl.handle.net/10447/219878.
Pełny tekst źródłaThe majority of solid tumors are characterized by aneuploidy that is believed to be the consequence of chromosomal instability (CIN). The mechanisms leading to aneuploidy and the pathway (s) that allows its tolerance are not completely understood. The Spindle Assembly Checkpoint (SAC) is a cellular surveillance mechanism that works to maintain the genomic balance in mitosis. Alterations of SAC components can induce aneuploidy but it is not clear if these defects are sufficient for tumorigenesis. In this process the genetic background of the cell plays an important role. It is known that p53 defects allow cells to quickly proliferate tolerating CIN. On the contrary, activation of wt-p53 counteracts aneuploidy. Less is known about the role of the p14ARF tumor suppressor to counteract aneuploidy. In this thesis, I investigate the relationship between some of the SAC genes that if depleted induce aneuploidy and tumor suppressor genes. First, to investigate the role of p14ARF to counteract aneuploidy it was ectopically expressed in HCT116 cells (near diploid) after MAD2 depletion a crucial component of the SAC. MAD2 posttranscriptional silencing induced high levels of aneuploid cells and aberrant mitosis that decreased when p14ARF was simultaneously expressed. In addition, p14ARF ectopic expression in MAD2-depleted cells induced apoptosis associated with increased p53 protein levels. This response was not detected in HCT116 p53KO cells suggesting that p14ARF counteracts aneuploidy activating apoptosis p53-dependent. Second, I wanted to probe the relationship between the motor protein CENP-E, which works only in the SAC signaling, and aneuploidy in human cells. To this aim I used two types of cells, human primary fibroblasts (IMR90) and near diploid cells (HCT116) lacking p14ARF, and analyzed the effects of CENP-E depletion up to four weeks. These experiments showed a different response for the two cell types. Aneuploidy was tolerated for longer times in cells lacking p14ARF expression rather than in primary cells. In addition the observations that the reduction of aneuploidy in IMR90 cells was proportional to the increase of p14ARF gene expression, and that its ectopic expression in HCT116 cells reduced aneuploidy confirm the ability of p14ARF to counteract aneuploidy. Third, to improve these results I generated HCT116 cells expressing a functional p14ARF to assess the effects of CENP-E depletion. Collectively, these results suggest that the tumor suppressor p14ARF may have an important role to contrast aneuploidy activating a p53-dependent apoptosis pathway and that it is generally involved to counterbalance aneuploidy induced by different stimuli.
Gretton, Svetlana. "Investigation of the functional role of the transcription factor, CTCF, in the regulation of human Bax and p14ARF genes". Thesis, University of Essex, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589445.
Pełny tekst źródłaChen, Jingyu. "Nucleolar stress stimulates the NF-kappaB pathway : mechanism underlying the proapoptotic effects of aspirin". Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28901.
Pełny tekst źródłaOzenne, Peggy. "Contrôle de la signalisation oncogénique du mutant L858R de l'EGFR par la protéine suppresseur de tumeur p14ARF dans les adénocarcinomes pulmonaires". Phd thesis, Université de Grenoble, 2011. http://tel.archives-ouvertes.fr/tel-00767340.
Pełny tekst źródłaLeduc, Camille. "Fonctions anti-prolifératives de la protéine suppressive de tumeur p14ARF dans les cancers broncho-pulmonaires : contribution de la protéine du rétinoblastome Rb". Université Joseph Fourier (Grenoble), 2005. http://www.theses.fr/2005GRE10078.
Pełny tekst źródłaLit is clearly established that the p14ARF tumour-suppressor protein belongs to a linear p14ARF /MDM2/p53 pathway that inhibits cell growth in response to oncogenic stimuli. However, our previous demonstration of a frequent co-inactivation of p14ARF and p53 proteins in human lung tumors led us to investigate the possibility that p14ARF could display p53-independent functions. Ln this study, we showed that p14ARF inhibits the growth of p53-null human tumoral pulmonary ceillines by inducing a G2 arrest that precedes apoptosis, and leading to the regression of lung tumours established into nude mice. Several studies have led us to consider the retinoblastoma protein (Rb) as a potential mediator of the p53-independent anti-proliferative activity of p14ARF. To test this hypothesis, we investigated the existence of direct relationships belween these Iwo proteins. Ln this setting, we showed that the Tip60-mediated Rb acetylation stimulates its proteasomal degradation and provided evidencethat p14ARF stabilizes Rb by preventing its Tip60-dependent acetylation. Ln addition, we present data indicating that hypoacetylated Rb accumulates in a p14ARF-dependent manner following a cell treatment with alkylating agents. Overall, our results situate p14ARF as a critical regulator of cell growth whatever the p53 status, and identify a new mechanism by which p 14ARF controls the Rb pathway to trigger its anti-proliferative activity
CILLUFFO, Danilo. "Identification of molecular markers involved in cellular response to aneuploidy in normal and tumor cells". Doctoral thesis, Università degli Studi di Palermo, 2020. http://hdl.handle.net/10447/395230.
Pełny tekst źródłaFauvin, Dominique. "Caractérisation de nouvelles fonctions du suppresseur de tumeurs p14ARF à travers deux exemples, le récepteur à activité tyrosine kinase ErbB3 et le facteur de transcription UBF1". Poitiers, 2009. http://www.theses.fr/2009POIT1406.
Pełny tekst źródłaHashemi, Jamileh. "Germline CDKN2A/ARF alterations in human melanoma /". Stockholm : Karolinska institutet, 2002. http://diss.kib.ki.se/2002/91-7349-148-9.
Pełny tekst źródłaHolzer, Kerstin [Verfasser], i Peter J. [Akademischer Betreuer] Goebell. "Auswertung von Häufigkeitsverteilungen und Korrelationen der Proteine Hdm2, P53, P63, P14ARF und P16INK4a im invasiven Harnblasenkarzinom an digitalisierten Tissue Mikroarrays / Kerstin Anna Holzer. Betreuer: Peter J. Goebell". Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2013. http://d-nb.info/1033030031/34.
Pełny tekst źródłaDi, Tommaso Anne. "Etude du suppresseur de tumeurs p14ARF chez les primates : identification des variations en N-terminal, et leurs impacts, sur la localisation de ARF et la régulation du cycle cellulaire". Poitiers, 2006. http://www.theses.fr/2006POIT2312.
Pełny tekst źródłaThe Alternative Reading Frame (ARF) tumor suppressor primarily inhibits cell proliferation by activating p53-dependent cell cycle arrest and/or apoptosis. To gain more insight into ARF function, we recently examined the first exon coding sequences of ARF from 14 different species of primates, including human, monkeys and apes. The sequences were nearly identical except for several discrete amino acid variations that distinguished human ARF from other primate forms of ARF. The impact of those changes on the biological activities of ARF was tested in this study. We found that conversion of Ala31 to Thr31, which is specific to human, enhanced ARF’s ability to upregulate p21Cip1 expression. By comparison, combined alteration of ARF amino acids Thr31 and Leu60 (T31L60) to Ala31 and His60 (A31H60) increased ARF-Mdm2 association. This work shows that some p14ARF residues impart specific effects on its biological activities that may influence the efficacy of ARF-mediated tumor suppression
Overkamp, Tim. "Bedeutung des p53-Signalwegs für Apoptoseaktivierung und Zellzyklusarrestregulation durch das p14 ARF Tumorsuppressorgen". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16619.
Pełny tekst źródłaBH3-only proteins, a pro-apoptotic subgroup of the Bcl-2 family of proteins, are central mediators of apoptosis signals by regulating the intrinsic apoptosis pathway. We have recently shown, that apoptosis triggered by the p14ARF tumour suppressor protein is mediated by the p53-dependent activation of the BH3-only protein Puma/Bbc3. Nevertheless, expression of p14ARF in p53-family deficient cells is capable of inducing both cell cycle arrest and apoptosis, but the signalling pathways initiated remain elusive. Here, we report that the BH3-only protein Bmf (Bcl-2 modifying factor) is involved in cell death in p53-deficient cells triggered by p14ARF. Expression of p14ARF leads to the induction of the PERK kinase, subsequent phosphorylation of eIF2α and activation of transcription factors ATF4 and CHOP. This signalling cascade is usually part of the ‘unfolded protein response’ (UPR), which is activated upon ER stress to reduce the amount of misfolded proteins by reduction of global protein translation initiation and upregulation of chaperones. Of note, p14ARF does not induce ER stress but activates the PERK‒CHOP pathway. ATF4 and CHOP transcription factors directly bind to the promotor region of bmf and induce its transcription. These data suggest that the PERK‒eIF2α‒ATF4‒CHOP signalling pathway may play a substantial role in mediating p14ARF-triggered apoptosis. This pathway could play the role of a ‘fail-safe’ mechanism that allows cells, even after loss of p53, to undergo apoptosis induced by upregulation of p14ARF by oncogenes.
Younes, Mohamad. "Etude des relations entre les mutations EGFR/KRAS et les altérations de la voie p53/p14arf et caractérisation d'une nouvelle cible thérapeutique, le complexe neurotensine et son récepteur1, dans les cancers bronchiques non à petites cellules". Phd thesis, Université Pierre et Marie Curie - Paris VI, 2012. http://tel.archives-ouvertes.fr/tel-00839459.
Pełny tekst źródłaKovi, Ramesh C. "Defining the Role of CtBP2 in p53-Independent Tumor Suppressor Function of ARF: A Dissertation". eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/433.
Pełny tekst źródłaFonseca, Maria Cristina Dias Ferrão. "P53, MDM2 and P14ARF immunohistochemical expression in retinoblastoma". Master's thesis, 2010. http://hdl.handle.net/10316/18584.
Pełny tekst źródłaIntroduction: Retinoblastoma is the most common primary ocular malignancy in pediatric age. Knudson proposed his two-hit model, allowing the distinction of retinoblastoma in two major classes: heritable and non-heritable. Retinoblastoma was first considered to arise from a well known mutation in the RB1 tumor-suppressor gene (chromosome 13q14). Currently, evidence supports that biallelic inactivation of RB1 gene is the initiating event, but not sufficient for fully malignant progression [1]. The hypothesis of altered expression of p14ARF-MDM2-p53 surveillance pathway components was proposed as an attempt to explain fully retinoblastoma development [2]. Previous studies proposed that p14ARF protein expression was undetectable, in contrast with Mdm2 protein overexpression in retinoblastoma [3]. Objectives: The aim of this study was to evaluate the immunohistochemical expression of p53 pathway components (p14ARF, Mdm2 and p53) in order to a better understanding of the molecular pathogenesis and differentiation of retinoblastoma. Additionally, it was attempted to correlate the expression of these proteins with retinoblastoma’s heritable pattern, Reese-Ellsworth staging and vital prognosis. Methods: A cohort of 24 retinoblastoma tissue samples from 22 enucleated cases was obtained from the registry of HUC’s Ophthalmic Pathology Laboratory. Clinical records were consulted to collect information including gender, age, heritable pattern, Reese-Ellsworth stage and prognosis. Immunohistochemistry was performed on formalin-fixed, paraffinembedded retinoblastoma tissue samples using primary antibodies against p53, p14ARF and Mdm2. Results: Positive p53, p14ARF and Mdm2 expression was obtained in 87.5% (21/24), 87.5% (21/24) and 95.8% (23/24) of the 24 samples, respectively. Overall, p53 protein expression was not positively correlated neither with p14ARF (p=0.343) nor Mdm2 expression P53,MDM2 AND P14ARF IMMUNOHISTOCHEMICAL EXPRESSION IN RETINOBLASTOMA 9 (p=1.000). In addition, p14ARF expression was mainly found in tissue samples that were positive for both p53 and Mdm2. Moreover, we did not obtain a positive relationship between p53, p14ARF and Mdm2 expression and the analyzed clinical parameters (heritable pattern, vital prognosis and Reese-Ellsworth staging). Conclusions: In our study, we obtained 87.4% of positive p14ARF nuclear and nucleolar expression and we even documented the presence of p14ARF overexpression in half of the cases, in opposition to previous reports [3]. According to our results, there was a Mdm2 overexpression in 79.2% of retinoblastoma samples, which supports the hypothesis that MDM2 overexpression may be an important element in retinoblastoma molecular pathogenesis [2,4]. The small cohort of patients involved in this study compromised the final results, which did not show any statistical significance. Further studies need to be performed in order to establish the true prognostic value of these histological markers, using a larger retinoblastoma patient’s population.
Freedberg, D. E., S. H. Rigas, J. Russak, W. Gai, M. Kaplow, I. Osman, F. Turner i in. "Frequent p16-independent inactivation of p14ARF in human melanoma". 2008. http://hdl.handle.net/10454/5973.
Pełny tekst źródłaIvanchuk, Stacey M. "Identification and characterization of novel p14ARF tumour suppressor binding partners". 2005. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=232762&T=F.
Pełny tekst źródłaHemmati, Philipp [Verfasser]. "Tumorbiologische Relevanz und Regulation des p14ARF Tumorsuppressorsignalweges / von Philipp Hemmati". 2010. http://d-nb.info/1010915339/34.
Pełny tekst źródłaHung, Chia, i 黃嘉宏. "The association between cellular expression of MDM2 and p14ARF with Chronic Kidney Disease". Thesis, 2012. http://ndltd.ncl.edu.tw/handle/98809748696984866714.
Pełny tekst źródła中山醫學大學
醫學研究所
100
Objectives According to Department of Health report of the rank of public mortality etiolgy, chronic kidney disease had been the tenth rank. Chronic kidney disease not only causes patient mortality by itself, Chronic kidney disease related morbidities also induce patient mortality(Wen, Cheng et al. 2008; Bowling, Feller et al. 2011). One of the pathogenesis of Chronic kidney disease was apoptosis, the correlation between apoptotic makers with acute kidney injury had been reported before(Kaushal, Basnakian et al. 2004; Bengatta, Arnould et al. 2009; Havasi and Borkan 2011), therefore, we studied if these apoptotic pathway makers also had the correlation to the severity of Chronic kidney disease on our kidney tissue samples. Methods We totally collect seventy Chronic kidney disease patients who received Nephroectomy due to all kinds of etiologies within three years. We retrospectively studies the correlation between Immunohistochemical stains of these kidney tissues by MDM2 and p14ARF with the clinical severity of Chronic kidney disease. Results We showed the glomerular and interstitial fibrosis scores had the significant difference between the advanced chronic kidney disease( eGFR < 45 ml/min/1.73 m2) and non- advanced chronic kidney disease( eGFR >= 45 ml/min/1.73 m2). In the area of normal tubular cytoplasm and atrophy tubular cytoplasm, p14ARF had stronger staining in the group of advanced chronic kidney disease( p vaule were 0.009 and 0.011 respectively,statistical significant difference). After further analysis, we found the patients who were over sixty five years- old, abnormal BMI( too light or over weight), had the diagnosis of Urothelial cell carcinoma (UCC), high serum Creatinine level and stronger staining p14ARF of normal tubular cytoplasm all had higher risk for advanced chronic kidney disease(Odds ratio and 95% Confidence Interval were 2.81 and 1.06-7.44; 66.00 and 6.08-716.18; 10.50 and 2.34-47.04; 3.75 and 1.08-13.07;558.00 and 48.24-6453.81;5.76 and 1.62-20.45). Conclusion We showed the Immunohistochemical stain of p14ARF over normal tubular cytoplasm area had positive correlation with the clinical severity of Chronic kidney disease.
Wang, Yu-Chien, i 王郁茜. "Etiological association of alterations in p53-hdm2-p14ARF pathway with lung tumorigenesis in Taiwan". Thesis, 2003. http://ndltd.ncl.edu.tw/handle/19243168942193336071.
Pełny tekst źródła國立臺灣師範大學
生物研究所
91
Lung cancer is the leading and second cause of cancer deaths among women and men in Taiwan, respectively. However, the molecular mechanisms involved in lung tumorigenesis in Taiwan remain poorly defined. There is increasing evidence that alterations in tumor suppressor genes and oncogenes are common in many forms of human cancer including lung cancer. We found that p53 gene mutation frequency was 17% in resected non-small cell lung cancers (NSCLC). However, p53 protein overexpression frequency was 48%. To further identify the molecular basis for this p53 immunohistochemical abnormality, we performed a genetic and epigenetic study of the p53 upstream proteins, p14ARF and hdm2, in NSCLC patients. Specimens of resected NSCLC from 113 patients were recruited in this study. Protein expression and mRNA expression of p14ARF and hdm2 were examined by immunoshitochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Methylation-based PCR assay was conducted to detect promoter methylation of the p14ARF gene. Loss of heterozygosity (LOH), homozygous deletion, and mutation of p14ARF gene were also examined. All data of p14ARF and hdm2 analyses were compared among patients with various clinicopathological parameters and with the p53 protein expression level. The data indicated that 45% and 41% lung cancer patients showed low or absent of hdm2 protein and mRNA expression, respectively. We also found that alternative splicing was the major mechanism which caused hdm2 gene alteration. In addition, we examined the frequency of protein expression of Akt kinase because Akt is known to associate with phosphorylation and nuclear localization of hdm2. The results indicated that the negative Akt kinase protein expression was correlated with negative hdm2 protein expression. With regard to p14ARF analyses, the data indicated that 34% and 31% lung cancer patients showed low or absent of p14ARF protein and mRNA expression, respectively. The frequency of p14ARF promoter hypermethylation, LOH, homozygous deletion, and mutation was 30%, 24%, 9% and 2%, respectively. We suggested that promoter hypermethylation was the major mechanism which caused p14ARF gene alteration. Note that 92% (35/38) patients with p53 overexpression showed absence or low expression of hdm2 protein and near overexpression of p14ARF protein. It indicated that the p53 overexpression was indeed induced by the dysregulation of the upstream proteins, hdm2 and p14ARF. Interestingly, most of the NSCLC patients with dysregulation of the p53-hdm2-p14ARF pathway were suffered late stage and SQ type of cancer. In addition, the patients with p53 overexpression had poor prognosis (P=0.013). The study was the first report which examines all possible alteration pathways in p53-hdm2-p14ARF gene/protein deregulation in the same series of NSCLC, and examines their relationship with the clinical data of NSCLC. In addition, it was also the first report on the alternative splicing of hdm2 mRNA in lung cancer. In conclusion, the alteration of p53-hdm2-p14ARF regulation pathway plays an important role in tumorigenesis of lung cancer in Taiwan, and could be potentially used as a molecular prognostic marker.
Wen-Ting, Yeh, i 葉文婷. "Analysis of gene alterations of p14ARF-p53 and p16INK4a-Rb pathways in bladder cancers". Thesis, 2001. http://ndltd.ncl.edu.tw/handle/87649100212305782273.
Pełny tekst źródła高雄醫學大學
醫學研究所
89
Bladder cancer is a significant health problem in the world. According to previously reports, alteration on chromosome 9 is the most common events in bladder cancer. The 9p21 gene cluster, harboring growth suppressive genes p14ARF and p16INK4a, play active roles in the p53 and Rb growth control pathways, respectively. p16INK4a is a cyclin- dependent kinase inhibitor functioning upstream Rb. p14ARF restrains cell growth by abrogating Mdm2 inhibition of the p53 activity and facilitates p53 mediated cell cycle arrest and apoptosis. Recent studies revealed that inactivation of p16INK4a/p14ARF gene might lead to cell carcinogenesis. In the present study, the mechanisms of inactivation of p16INK4a and p14ARF genes in bladder cancers were analyzed. The relative contribution of p14ARF/p53 and p16INK4a/Rb pathways in bladder cancer development was also evaluated. In this study, homozygous deletions of the p16INK4a and p14ARF genes were analyzed in 53 human bladder cancers by using Southern hybridization. The results showed that homozygous deletion of p16INK4a gene was observed in 12 (23%) samples. In contrast, a relatively higher percentage (43%, 23/53) of samples showed homozygous deletions of p14ARF. In addition, most of the p14ARF gene deletions occurred exclusively on the exon 1β region (91%, 21/23). However, only 2 samples contained deletion in exon 1β, 1α and exon 2. We also found that p14ARF gene deletion in well and morderate differentiated tumors and poor differentiated tumors were 6 (27%) and 17 (63%) respectively. PCR- SSCP and sequencing were performed to analyze the mutation status. Results showed that no mutations were detected in exon 1αand 1β in any cases. Only one mutation in exon 2 cause a missense mutation in the p16INK4a and p14ARF reading frame (2.5%;1/40) was found. This mutation was identified in p16INK4a codon 108 (GAT→CAT), resulting in a change of aspartic acid to histidine. The mutation is inside the ankyrin repeat motifs in a region that is required for the protein to bind and inhibit CDK4. The same mutation in the p14ARF open reading frame was at codon 122 (CGA→CCA), resulting in a change of arginine to proline. DNA methylation patterns in the CpG islands of the p16INK4a and p14ARF gene were determined by MSP. p16INK4a CpG island methylation was found in 24 of 40 (60%) tumors, but no methylation was detected in p14ARF in any cases. An analysis of the p16INK4a and p14ARF mRNA expression was carried out by RT-PCR. Results showed that p16INK4a mRNA expression was not detected in 27 of 49 (55%) tumors, including 12 cases harboring deletion and 15 cases containing methylation. However, expression of the p16INK4a gene was also observed in 7 cases with DNA methylation, suggesting partial methylation on one allele. Suppressed p14ARF mRNA expression was detected in 28 of 49 tumors (57%). But, 5 of the 28 samples with suppressed p14ARF mRNA expression contained no detectable alteration. Uncoupling between p14 transcript and p14ARF alteration suggest a novel mechanism of inactivation existed. In this study immunohistochemistry examined the expression of P16 and P14 together with RB and P53 status in bladder cancers. The results indicated that P14 was frequently absent in bladder cancers (27/39, 69%). Abnormal expression of P53 was also observed in 27 of 39 (69%) samples. Concomitant absent P14 expression and staining of P53 was frequently observed in bladder cancer (17/39; 44%). P16 protein was undetectable in 25 of 39 (64%) samples. Absence RB protein expression was seen in 23% (9/39), however, overexpression was frequently observed in 38% (15/39) samples. Furthermore, result indicated that RB protein unexpression was significantly correlated in invasive bladder cancer. Concomitant P16 and P53 protein abnormal expression was frequently observed also in bladder cancer (44%, 17/39). Taken together, the results showed that in cases of bladder cancer, at least one protein was altered, and alterations of tumors in both p16INK4a/Rb and p14ARF/p53 pathways was more often (77%, 30/39) than tumors with one or no alteration of these two major pathways. Our results show that in bladder cancers, p14ARF is a primary target of homozygous deletion, whereas p16INK4a is the hotspot of methylation of the 9p21 gene cluster. The frequent inactivation of the p14ARF and p16INK4a genes may be an important mechanism for the dysfunction of both the Rb and p53 growth regulatory pathways during bladder cancer development.
Liao, Chien-Huang, i 廖建皇. "Molecular Mechanisms of 1-Nitropyrene, Benezo [a] pyrene, p14ARF and Taxol mediated Telomerase Regulation in H1299 NSCLC Cell Line". Thesis, 2002. http://ndltd.ncl.edu.tw/handle/93833661872611337847.
Pełny tekst źródła中山醫學大學
毒理學研究所
90
貳、英文摘要 Telomerase activity is not detectable in most somatic cell but is upregulated in 85~95% of human canner, which suggests important role of telomerase in neoplastic transformation. Telomerase revese transcriptase was the determinant rate-limiting step in telomerase regulation, and its active promoter activity was involved in telomerase reactivation. Therefore we have cloned the telomerase revese transcriptase promoter (h.TERT-p548). In addition , we co-transfected a series of constructs containing unidirectionally delected fragments: h.TERT-p-212~+50 (core promoter)、h.TERT-p -196~+50 (deleted SP1 site)、h.TERT-p-177~+50 (deleted SP1 and c-MYC site)、h.TERT-p-155~+50 (deleted SP1、c-MYC and AP-2 site), respectively, to examine whether B[a]P、1-NP、p14ARF and taxol regulated telomerase activation through those transcription factors. In the present study, we first employed TRAP and RT-PCR to elucidate whether the regulation of telomerase activity and h.TERT mRNA expression in human NSCLC cell by treatment with B[a]P、1-NP and p14ARF . The telomerase activation was not influence by treament with B[a]P、1-NP and p14ARF ;h.TERT mRNA level was increased 1~2 fold by low concentration of B[a]P and 1-NP , and that was increased 1~1.5 fold by treatment with p14ARF .h.TERT-p548 was activated by low concentration of B[a]P, and repressed by 1-NP、p14ARF and taxol when experiment with transient transfection and luciferase reporter assay . In addition , they did not modulate these transcription factor to regulate h.TERT transcription activation. Significantly, after we alone transfecting h.TERT-p-177 or h.TERT-p-155 plasmid DNA , each still expressed 50~60% transcription activation.It indicated that except for c-Myc, AP-2 and NF-E2 have the ability to regulate telomerase reactivation. Finally our flow cytometric studed show that B[a]P、1-NP and p14ARF slightly increase G0/G1 percentage , and taxol cause cell cycle arrest in G2/M phase leading apoptosis . Furthermore, B[a]P、1-NP、p14ARF and taxol can induce cytotoxicity in H1299 and casue cell death using MTT and colony formation assay . In summary, this study provides data showing that B[a]P、1-NP、p14ARF and taxol all were able to regulate h.TERT transcriptionactivation , but independently of c-Myc . Maybe they dependent on other transcription factors to regulate telomerase reactivation.