| Research Abstract |
Mutations in the p53 tumor suppressor gene occur in about 50% of all human tumors, making it the most frequent target for genetic alterations in cancer. p53 acts as a transcriptional activator, and exert its biological activity by activation of genes involved in inhibition of cell cycle progression and in induction of apoptosis. Recently, it has been shown that activation of oncogenes such as mos and ras evokes a DNA damage response, which results in p53 activation. During the early tumorigenic stages, aberrant oncogene activation can give rise to 'oncogenic stress', which evokes a p53-mediated counter-response to eliminate hazardous cells through the induction of apoptosis or senescence. Therefore, during oncogenesis, p53 inhibition is crucial for the survival and maintenance of such oncogene-expressing cells. In addition, oncogenesis in humans is a multi-step process and these steps reflect genetic alterations in several oncogenes and tumor suppressor genes. Several lines of evidence
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indicate functional inactivation in p53 genes do not usually occur until late stage of this process. Therefore, in early stage of oncogenesis, oncogene-activated cells are required for growing against activated p53. However, mechanisms underlying this process are still unclear.
In this context, we found that hedgehog signal inhibits p53 activity. We also found that hedgehog signal induces phosphorylation of p53-specific ubiquitin ligase Mdm2, and activates degradation of p53-protein. The Hedgehog signal partially inhibited the p53-dependent apoptosis or cell growth inhibition of oncogene-expressing MEFs. In addition, we found that accumulation of p53 is inhibited by the Hh signal in several human cancer cell lines. Therefore, the Hh pathway may be a powerful accelerator of oncogenesis, which activates cell proliferation and inhibits the p53-mediated anti-cancer barrier induced by oncogenic stress. In addition, we also found a link between the tumour suppressor p53, transcription factor NF-κB, and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKKα and IKKβ and subsequent NF-κB activity are enhanced. Activation of NF-κB, by loss of p53, leads to an increased rate of aerobic glycolysis. Oncogenic Ras-induced cell transformation and acceleration of aerobic glycolysis in p53-deficient cells were suppressed in the absence of p65/NF-κB expression. These results indicated that p53 restricts activation of the IKK-NF-κB pathway through suppression of glycolysis. Less
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