Browsing by Subject "P16(ink4a)"
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Item Open Access p53 but not p16(INK4a) induces growth arrest in retinoblastoma-deficient hepatocellular carcinoma cells(Elsevier, 2000-08) Morel, A. P.; Unsal, K.; Cagatay, T.; Ponchel, F.; Carr, B.; Ozturk, M.Background/Aim: Both p16(INK4a) and p53 proteins are negative regulators of the cell cycle. In human hepatocellular carcinomas (HCC), the loss of function of p53, retinoblastoma (pRb) and p16(INK4a) genes by different mechanisms has been largely documented, but their hepatocellular effects are poorly known. We compared the growth-inhibitory effects of p16(INK4a)and p53 proteins in Hep3B cell line-derived clones. Methods: Cells were transfected with inducible p16(INK4a) and p53 expression vectors, and stable clones were analyzed for transgene expression by Western blotting and immunoperoxidase staining. Effects on cell growth were analyzed by in vitro growth assay, thymidine incorporation and flow cytometry. Biochemical effects of p53 were tested by Northern blotting of p21(Cip1) transcripts and by Western blotting of p21(Cip1) mdm-2, bax, cyclin-dependent kinase 2 and cyclin E proteins. The pRb protein was studied by Western blotting and immnunoprecipitation assays. Results: The induction of p16(INK4a) protein expression did not affect in vitro growth of cells. In contrast, p53 protein in its wild-type conformation provoked a growth arrest accompanied by transactivation of p21(Cip1) gene and accumulation of p21(Cip1), bax and mdm-2 proteins, p53-induced growth arrest was due to a cell cycle arrest at the GI/S transition, probably mediated by p21(Cip1) protein, which inhibits cyclin-dependent kinase 2/cyclin E complexes. Conclusions: The lack of detectable pRb protein and resistance of cells to p16(INK4a) strongly suggest that p53 is able to arrest the growth of HCC cells by a mechanism independent of 'p53-retinoblastoma pathway'. These findings are applicable to HCC with abberrations of both p53 and pRb genes, and may not represent the universal effects of p53 in hepatic cells.Item Open Access Senescence and immortality in hepatocellular carcinoma(Elsevier, 2009-10-01) Ozturk, M.; Arslan-Ergul, A.; Bagislar, S.; Senturk, S.; Yuzugullu, H.Cellular senescence is a process leading to terminal growth arrest with characteristic morphological features. This process is mediated by telomere-dependent, oncogene-induced and ROS-induced pathways, but persistent DNA damage is the most common cause. Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation. p53 plays a relay role between DNA damage sensing and p21(Cip1) activation. pRb arrests the cell cycle by recruiting proliferation genes to facultative heterochromatin for permanent silencing. Replicative senescence that occurs in hepatocytes in culture and in liver cirrhosis is associated with lack of telomerase activity and results in telomere shortening. Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a). Moreover, they re-express telomerase reverse transcriptase required for telomere maintenance. Thus, senescence bypass and cellular immortality is likely to contribute significantly to HCC development. Oncogene-induced senescence in premalignant lesions and reversible immortality of cancer cells including HCC offer new potentials for tumor prevention and treatment. (C) 2008 Elsevier Ireland Ltd. All rights reserved.