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

p53抑癌作用机制分析；

基本信息

批准号：
16390084
负责人：
TANAKA Nokuyuki
金额：
$ 9.41万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

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

p53肿瘤抑制基因的突变发生在所有人类肿瘤的约50％中，使其成为癌症遗传改变的最常见目标。 p53充当转录激活剂，并通过激活涉及细胞周期进展和凋亡诱导的基因来发挥其生物学活性。最近，已经表明，诸如MOS和RAS等癌基因的激活会引起DNA损伤反应，从而导致p53激活。在早期的致瘤阶段，异常的致癌基因激活会引起“致癌应激”，从而引起p53介导的反应，从而通过诱导凋亡或感应性来消除有害细胞。因此，在肿瘤发生期间，p53抑制对于这种表达癌基因的细胞的存活和维持至关重要。此外，人类的肿瘤发生是一个多步骤过程，这些步骤反映了几种癌基因和肿瘤抑制基因的遗传改变。几条证据……在p53基因中的功能灭活中更多的证据通常直到该过程的后期才出现。因此，在肿瘤发生的早期阶段，与激活的p53生长需要致癌基因激活的细胞。但是，此过程的基础机制仍不清楚。在这种情况下，我们发现刺猬信号抑制了p53活性。我们还发现，刺猬信号诱导p53特异性泛素连接酶MDM2的磷酸化，并激活p53-蛋白质的降解。刺猬信号部分抑制了p53依赖性的细胞凋亡或细胞生长抑制表达癌基因的MEF。此外，我们发现p53的积累在几种人类癌细胞系中抑制了HH信号。因此，HH途径可能是肿瘤发生的强大加速器，它激活细胞增殖并抑制由致癌应激引起的p53介导的抗癌屏障。此外，我们还发现了肿瘤抑制p53，转录因子NF-κB和糖酵解之间的联系。在缺陷的原代培养细胞中，IKKα和IKKβ的激酶活性以及随后的NF-κB活性得到了增强。 NF-κB的激活通过p53的损失导致有氧糖酵解的速率增加。在没有p65/NF-κB表达的情况下，抑制了致癌性RAS诱导的细胞转化和有氧糖酵解的加速度。这些结果表明，p53通过抑制糖酵解限制了IKK-NF-κB途径的激活。较少的