抑癌基因p53在特定高温下作用研究

细胞程序死亡主要有三种形式：细胞凋亡、细胞自噬和细胞程序坏死。抑癌基因p53可被DNA损伤激活，诱导损伤的细胞停止分裂或走向凋亡，从而确保遗传物质的稳定性。p53突变不仅容易导致肿瘤发生，而且此种癌细胞对于化疗和放疗极不敏感。p53还会被高温激活，但高温下p53起着怎样作用还未有报道。我们在用特定高温处理野生型和p53突变体斑马鱼胚胎时，惊奇发现野生型在此温度下的成活率远远高于突变体，并且在人类细胞系中获得类似的结果（未发表）。在此项目中我们将：.1）利用斑马鱼和人类细胞系，揭示p53在此高温下通过抑制哪种死亡方式来促进细胞成活及其分子机理；.2）利用人类癌细胞系在裸鼠中移植成瘤体系，探讨高温特异性抑制p53突变的癌细胞生长的作用。.研究结果不但首次揭示高温激活p53起着促进细胞成活的作用及其作用机制，并且为癌细胞中p53突变的患者提供一个崭新的治疗策略。

Tumor repressor p53 is activated in response to DNA damage stresses. Activated p53 triggers cell cycle arrest in cells with less DNA damage to repair damage and apoptosis in cells with severe DNA damage. Thus it ensures genomic stability. p53 is mutated in more than 50% of human cancer cells. Mutations in p53 not only predispose an organism to cancer, but also lead these tumors to respond poorly to radio- or chemo-therapy. .There are three main types of programmed cell death including: apoptosis, programmed necrosis and autophagy. Autophagy is a cellular process that involves degradation and recycling long-lived proteins and organelles, in lysosomes. It is a cell survival mechanism to maintain homeostasis, quality control, defense against intra- and extracellular insults, and the cellular energetic balance. If autophagic activity is insufficient, cells will accumulate long-lived proteins and defective organelles which finally leads cell apoptosis. However, if the proteins and organelles destroyed by autophagy are beyond a certain threshold, autophagic cell death will occur. Degradation of proteins and organelles by lysosomes can be achieved by at least three different mechanisms: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). CMA is responsible for the degradation of a subset of cytosolic proteins carrying a consensus motif in their amino acid sequence, similar to KFERQ, in a stress condition such as nutrient deprivation, however, little is known about the consequence of excessive CMA activation. .p53 plays a dual role in the process of macroautophagy, nuclear p53 promotes macroautophagy by regulating gene expression, whereas cytoplasmic p53 suppresses macroautophagy. However, whether p53 plays a role in CMA is unclear. .It was known that p53 is also activated in response to heat shock stress. To investigate what role p53 plays in high temperature conditions, we incubated zebrafish p53M214K mutant and wild type (WT) embryos at a high temperature for continuously growing. Very interestingly, we found that WT embryos (still with about 45% viability at 28 hour post treatment hpt for instance) were much more tolerance to the high temperature than p53M214K mutant embryos (with 100% mortality at 28 hpt) at the high temperature (unpublished). The results were further confirmed in human cell lines(unpublished data). The aims of this project are as follow:.1. To identify in what mechanisms for p53 to promote cell survival in the high temperature stress;.2. To investigate whether the high temperaturre treatment is able to suppress tumor growth of p53-deficient xenografts by transplantation of human cancer cells in immunocompromised mice..The discoveries of this research will not only be the first one to reveal a new function of p53 to promote cell survival at a high temperature and molecular mechanisms behind of it, but also be highly appropriate to adopt thermotherapy to treat p53-deficient tumors/cancers.