Browsing by Subject "p53"
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Item Open Access Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation(John Wiley & Sons, 2011) Gürsoy-Yüzügüllü, Özge; Yüzügüllü, Haluk; Yılmaz, Mustafa; Öztürk, MehmetBackground: Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths. Aflatoxins, which may play a causative role in 5-28% of HCCs worldwide, are activated in liver cells and induce principally G→T mutations, including the TP53 codon 249(G→T) hotspot mutation. The DNA damage checkpoint response acts as an antitumour mechanism against genotoxic agents, but its role in aflatoxin-induced DNA damage is unknown. Aim: We studied the DNA damage checkpoint response of human cells to aflatoxin B1 (AFB1). Methods and results: The treatment of HepG2 hepatoma cells with mutation-inducing doses (3-5μmol/l) of AFB1 induced DNA adducts, 8-hydroxyguanine lesions and DNA strand breaks that lasted several days. Persistent phospho-H2AX and 53BP1 foci were also detected, but cell growth was not affected. AFB1-exposed HepG2 cells formed phospho-H2AX and 53BP1 foci, but failed to phosphorylate both Chk1 and Chk2. Huh7 hepatoma and HCT116 colorectal cancer cell lines also exhibited a similarly incomplete checkpoint response. p53 phosphorylation also failed, and AFB1-exposed cells did not show p53-dependent G1 arrest or a sustained G2/M arrest. These observations contrasted sharply with the fully functional DNA damage response of cells to Adriamycin. Cotreatment of cells with AFB1 did not inhibit p53 and p21Cip1 accumulation induced by Adriamycin. Thus, the deficient checkpoint response to AFB1 was not due to an inhibitory effect, but could be explained by an inefficient activation. Conclusion: Genotoxic doses of AFB1 induce an incomplete and inefficient checkpoint response in human cells. This defective response may contribute to the mutagenic and carcinogenic potencies of aflatoxins.Item Open Access A chronic myeloid leukemia-like syndrome case with del (12) (p12) in a Li-Fraumeni syndrome family(Blackwell Publishing Ltd, 2005) Guran, Ş.; Beyan, C.; Nevruz, O.; Yakıcıer, C.; Tunca, Y.Li-Fraumeni syndrome is a familial cancer syndrome characterized by different tumors and hereditary p53 mutations. Here, a chronic myeloid leukemia-like syndrome case in a Li-Fraumeni syndrome family with del (12) (p12) cytogenetic abnormality was presented. A hereditary p53 mutation (pro309ser) supported the Li-Fraumeni syndrome diagnosis in this family. This syndrome was characterized by the clonal myeloproliferative accumulation in bone marrow and peripheral blood with negative bcr/abl gene rearrangement finding. The etiology of this rare syndrome is still unclear. This is the only chronic myeloid leukemia-like syndrome case reported in a Li-Fraumeni syndrome family. Del (12) (p12) was observed in leukemias except chronic myeloid leukemia-like syndrome. The deletion in chromosome 12pl2 with hereditary p53 mutation should have a critical role in chronic myeloid leukemia-like syndrome etiology in our case. © 2005 Blackwell Publishing Ltd.Item Open Access Concomitant inactivation of p53 and Chk2 in breast cancer(Nature Publishing Group, 2002) Sullivan, A.; Yuille, M.; Repellin, C.; Reddy, A.; Reelfs, O.; Bell, A.; Dunne, B.; Gusterson, B. A.; Osin, P.; Farrell, P. J.; Yulug, I.; Evans, A.; Ozcelik, T.; Gasco, M.; Crook, T.Item Open Access Genetic aspects of hepatocellular carcinogenesis(1999) Ozturk, M.Hepatocellular carcinoma (HCC) is linked etiologically to viruses (hepatitis B virus [HBV] and hepatitis C virus [HCV]), chemical carcinogens (i.e., aflatoxins), and other environmental and host factors causing chronic liver injury. Some hepatoblastomas may be linked to inherited gene mutations, but adult hereditary HCC appears to be rare. HCCs display gross genomic alterations, including DNA rearrangements associated with HBV DNA integration, loss of heterozygosity, and, less importantly, chromosomal amplifications and loss of imprinting. Many genes with somatic mutations have now been identified in these tumors. Most frequently involved genes are tumor suppressor genes such as p53, M6P/IGF2R, β-catenin, p16INK4A, and retinoblastoma genes. Most identified mutations are somatic, but germline mutations of p16INK4A, APC, and BRCA2 have also been reported. Oncogenic activation of several cellular genes such as cyclin D and cyclin A have been described in HCC, but the possible implication of candidate viral oncogenes (i.e., X protein of HBV) is still debated. A comprehensive analysis of all the genetic changes described for HCC demonstrates that at least four different growth regulatory pathways are altered in these tumors. However, each pathway appears to be implicated in a limited fraction of these tumors, suggesting that HCCs are genetically heterogenous neoplasms. This genetic heterogeneity correlates with the heterogeneity of etiologic factors implicated in HCC.Item Open Access In silico analysis of mutant p53(R249S) oncogenicity in hepatocellular carcinoma(Bilkent University, 2007) Ovezmuradov, GuvanchmuradOncogenic properties of mutant p53 proteins still stand as an ill-known subject, and the mechanism responsible for this phenomenon remains to be uncovered. This thesis aims to uncover the effect of p53 codon R249S ((AGG→AGT, arginine to serine) mutation on the development of hepatocellular carcinoma (HCC) through high throughput transcriptomics analysis using oligonucleotide arrays. We compared the expression profiles of HepG2 cells carrying wt and mutant p53(R249S). Microarray data analysis revealed a molecular signature consisting of 84 differentially regulated genes, showing that the expression of mutant p53(R249S) in HepG2 cells resulted in a distinct expression profile. Furthermore, mapping these significant differentiallyexpressed genes to the p53 interaction network revealed a putative interaction network representing functional outcomes of p53(R249S) expression in the context of diverse molecular interactions. Our results clearly demonstrated that several Hepatocyte Nuclear Factors (HNF1A, HNF4A and HNF6) could play an essential role in mediating mutant p53 oncogenic activity in HCC, as the key molecules of the gene network.Item Open Access A monoclonal antibody against DNA binding helix of p53 protein(Nature Publishing Group, 2001) Yolcu, E.; Sayan, B. S.; Yağci, T.; Cetin Atalay, R.; Soussi, T.; Yurdusev, N.; Ozturk, M.Three monoclonal antibodies (Mabs) were generated against p53 DNA-binding core domain. When tested by immunoprecipitation, Western blot and immunofluorescence techniques, Mab 9E4, as well as 7D3 and 6B10 reacted with both wild-type and various mutant p53 proteins. The epitopes recognized by Mabs 7D3, 9E4 and 6B10 were located respectively within the amino acid residues 211-220, 281-290 and 291-300 of human p53 protein. The epitope recognized by 9E4 Mab coincides with helix 2, also called p53 DNA binding helix, which allows the direct contact of the protein with its target DNA sequences. This antibody may be useful to study transcription-dependent and transcription-independent activities of wild-type and mutant p53 proteins.Item Open Access p53 mutation as a source of aberrant β-catenin accumulation in cancer cells(2002) Cagatay, T.; Ozturk, M.β-catenin is involved in both cell-cell interactions and wnt pathway-dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of β-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of β-catenin through Axin1- and APC-dependent phosphorylation by CKI and GSK-3β. Deregulation of β-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of β-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (β-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display β-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant β-catenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type β-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and β-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of β-catenin in cancer cells.Item Open Access Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells(National Academy of Sciences, 2006) Ozturk, N.; Erdal, E.; Mumcuoglu, M.; Akcali, K. C.; Yalcin, O.; Senturk, S.; Arslan-Ergul, A.; Gur, B.; Yulug, I.; Cetin Atalay, R.; Yakicier, C.; Yagci, T.; Tez, M.; Ozturk, M.Tumor cells have the capacity to proliferate indefinitely that is qualified as replicative immortality. This ability contrasts with the intrinsic control of the number of cell divisions in human somatic tissues by a mechanism called replicative senescence. Replicative immortality is acquired by inactivation of p53 and p16INK4a genes and reactivation of hTERT gene expression. It is unknown whether the cancer cell replicative immortality is reversible. Here, we show the spontaneous induction of replicative senescence in p53-and p16 INK4a-deficient hepatocellular carcinoma cells. This phenomenon is characterized with hTERT repression, telomere shortening, senescence arrest, and tumor suppression. SIP1 gene (ZFHX1B) is partly responsible for replicative senescence, because short hairpin RNA-mediated SIP1 inactivation released hTERT repression and rescued clonal hepatocellular carcinoma cells from senescence arrest. © 2006 by The National Academy of Sciences of the USA.Item Open Access TP53 mutations in familial breast cancer: Functional aspects(John Wiley & Sons, Inc., 2003) Gasco, M.; Yulug, I. G.; Crook, T.Mutation in p53 (TP53) remains one of the most commonly described genetic events in human neoplasia. The occurrence of mutations is somewhat less common in sporadic breast carcinomas than in other cancers, with an overall frequency of about 20%. There is, however, evidence that p53 is mutated at a significantly higher frequency in breast carcinomas arising in carriers of germ-line BRCA1 and BRCA2 mutations. Some of the p53 mutants identified in BRCA1 and BRCA2 mutation carriers are either previously undescribed or infrequently reported in sporadic human cancers. Functional characterization of such mutants in various systems has revealed that they frequently possess properties not commonly associated with those occurring in sporadic cases: they retain apoptosis-inducing, transactivating, and growth-inhibitory activities similar to the wild-type protein, yet are compromised for transformation suppression and also possess an independent transforming phenotype. The occurrence of such mutants in familial breast cancer implies the operation of distinct selective pressures during tumorigenesis in BRCA-associated breast cancers.