Analysis of the mechanism underlying tumor suppressive effect of p53 ; its role in the regulation of apoptosis

肿瘤抑制基因p53的突变发生在大约50%的人类肿瘤中，使其成为癌症基因改变的最常见目标。P53作为一种转录激活因子，通过激活参与抑制细胞周期进程和诱导细胞凋亡的基因来发挥其生物活性。最近有研究表明，癌基因如mos和ras的激活会引起DNA损伤反应，从而导致p53的激活。在早期的致瘤阶段，异常的癌基因激活可引起“致癌应激”，引起p53介导的对抗反应，通过诱导细胞凋亡或衰老来消除有害细胞。因此，在肿瘤发生过程中，抑制p53对于表达癌基因的细胞的生存和维持至关重要。此外，人类的肿瘤发生是一个多步骤的过程，这些步骤反映了几种致癌基因和肿瘤抑制基因的遗传改变。更多的证据表明，p53基因的功能失活通常直到该过程的后期才发生。因此，在肿瘤发生的早期，癌基因激活的细胞需要对抗活化的p53生长。然而，这一过程的机制尚不清楚。在这种情况下，我们发现hedgehog信号抑制p53活性。我们还发现，hedgehog信号诱导p53特异性泛素连接酶Mdm2的磷酸化，并激活p53蛋白的降解。Hedgehog信号部分抑制表达癌基因的mef的p53依赖性凋亡或细胞生长抑制。此外，我们发现在几种人类癌细胞系中，p53的积累受到Hh信号的抑制。因此，Hh通路可能是肿瘤发生的强大加速器，激活细胞增殖，抑制p53介导的致癌应激诱导的抗癌屏障。此外，我们还发现肿瘤抑制因子p53、转录因子NF-κB和糖酵解之间存在联系。在p53缺失的原代培养细胞中，IKKα和IKKβ的激酶活性以及随后的NF-κB活性增强。p53缺失导致NF-κB活化，导致有氧糖酵解速率增加。在缺乏p65/NF-κB表达的情况下，p53缺陷细胞的致癌ras诱导的细胞转化和有氧糖酵解的加速受到抑制。这些结果表明p53通过抑制糖酵解来限制IKK-NF-κB通路的激活。少

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 … More 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