p53调控NADPH代谢的机制研究

This proposal aims to further define the critical role of the tumor suppressor p53 in the regulation of NADPH metabolism and biosynthesis, as well as the consequences of the loss of this function in tumor pathogenesis. p53 is the most frequently mutated gene in human cancers, and its inactivation is critical for the proliferation of tumor cells. Being able to understand the mechanism by which p53 suppresses tumorigenesis has been a central objective in cancer biology, one which has important implications in the treatment of cancer. Tumor cells markedly reprogram nutrient metabolism and rapidly accumulate biomass to fuel proliferation. Based on our preliminary results, this proposal focuses on NADPH-generating enzymes isocitrate dehydrogenase 1 and 2 (IDHs). We plan to investigate the dynamic interplays between p53 and IDHs. Our central hypothesis is that mutual regulation between IDHs and p53modulates key metabolic processes and contributes top53-mediated tumor suppression. We propose three specific aims:(1) elucidate the role of p53 in regulating IDHs,and the p53/IDHs pathway in NADPH and reductive glutamine metabolism; (2) define the role of IDHs in regulating p53 activation, cell proliferation, and senescence. The proposed studies will improve our understanding of key aspects of metabolic regulation and their link to p53-mediated cell fate decision, and may provide a rationale for targeting these NADPH-generating enzymes as a new therapy for cancer.

p53基因是迄今为止发现的在人类肿瘤中发生突变频率最高的基因。虽然p53早在30年前已经被发现，但p53抑制肿瘤的机制仍然是个未解之谜，探索这一奥秘一直是肿瘤研究领域内的热点之一。近几年研究证明， p53参与了肿瘤代谢的调控过程。我们研究发现， p53直接调控了细胞内磷酸戊糖代谢途径和苹果酸酶通路，影响了细胞内NADPH代谢和肿瘤细胞生长。而且，我们最新初步实验结果表明，p53影响了NADPH代谢中的异柠檬酸脱氢酶（IDHs)的表达。基于以上发现，在本课题中，我们拟探讨以下主要问题： 1）p53调控IDHs 的分子机制，以及p53调控IDHs对细胞内NADPH 和谷氨酰胺代谢的影响； 2）IDHs反馈调控p53的机制，及其对细胞增殖和衰老的影响。通过对以上问题的研究，使得我们能够对肿瘤代谢途径和p53介导的细胞命运之间的联系有更加深入的理解，并为治疗癌症提供新的思路。

p53基因是迄今为止发现的在人类肿瘤中发生突变频率最高的基因。虽然p53早在30年前已经被发现，但p53抑制肿瘤的机制仍然是个未解之谜，探索这一奥秘一直是肿瘤研究领域内的热点之一。近几年研究证明， p53参与了肿瘤代谢的调控过程。. 我们研究发现， p53直接调控了细胞内磷酸戊糖代谢途径和苹果酸酶通路，影响了细胞内NADPH代谢和肿瘤细胞生长。而且我们最新初步实验结果表明，p53影响了NADPH代谢中的异柠檬酸脱氢酶（IDHs)的表达。. 基于以上发现，在本课题中，我们拟探讨以下主要问题：. 1）p53调控IDHs 的分子机制，以及p53调控IDHs对细胞内NADPH 和谷氨酰胺代谢的影响；. 2）IDHs反馈调控p53的机制，及其对细胞增殖和衰老的影响。.通过对以上问题的研究，使得我们能够对肿瘤代谢途径和p53介导的细胞命运之间的联系有更加深入的理解，并为治疗癌症提供新的思路。