The feedback loop between ferredoxin reductase and the p53 family in tumor suppression

项目摘要 抑癌基因P53家族由P53、P63和P73组成。P53家族蛋白 主要通过其转录靶点作为肿瘤抑制因子。我们和其他人展示了 铁氧还蛋白还原酶(FDXR)是由P53、P63和P73直接诱导的。初步调查 结果显示，FDXR的异位表达增加，而FDXR基因的部分破坏 降低肿瘤细胞对DNA损伤诱导的细胞凋亡的敏感性 举止。为了研究FDXR的生物学功能，我们开展了一项初步研究，通过 生成FDXR缺陷细胞和小鼠模型。我们发现FDXR缺乏 促进铁调节蛋白2(IRP2)的表达。我们还发现，细胞中缺乏 FDXR显示线粒体中铁超载。最有趣的是，我们展示了细胞 缺乏FDXR的患者也存在P53和P73的表达缺陷。相反，p63的表达是 在FDXR缺陷细胞中增加。此外，FDXR/-小鼠的寿命较短， 自发性肿瘤发生率高。这些观察结果促使我们假设 FDXR-P53家族通路是肿瘤抑制所必需的。为了测试这一点，我们将确定： (1)FDXR如何调控P53，以及FXR-P53环在肿瘤抑制中的作用； FDXR如何调控p63以及FDXR-p63环在肿瘤抑制中的作用； P73是如何被FDXR调控的，以及FDXR-p73环在肿瘤抑制中的作用。

Project Summary The p53 family of tumor suppressors is consisted of p53, p63, and p73. The p53 family proteins act as a tumor suppressor primarily through their transcriptional targets. We and others showed that ferredoxin reductase (FDXR) is induced directly by p53, p63 and p73. Initial investigations showed that ectopic expression of FDXR increases, whereas partial disruption of the FDXR gene decreases, the sensitivity of tumor cells to DNA damage-induced apoptosis in a p53-dependent manner. To investigate the biological function of FDXR, we carried out a pilot study by generating FDXR-deficient cells and mouse models. We showed that FDXR deficiency promotes iron regulatory protein 2 (IRP2) expression. We also showed that cells deficient in FDXR exhibit iron overload in the mitochondria. Most interestingly, we showed that cells deficient in FDXR are also deficient in p53 and p73 expression. In contrast, p63 expression is increased in FDXR-deficient cells. Furthermore, FDXR+/- mice have a short lifespan along with high incidence of spontaneous tumors. These observations prompt us to hypothesize that the FDXR-p53 family pathway is necessary for tumor suppression. To test this, we will determine: (1) how p53 is regulated by FDXR and the role of the FDXR-p53 loop in tumor suppression; (2) how p63 is regulated by FDXR and the role of the FDXR-p63 loop in tumor suppression; (3) how p73 is regulated by FDXR and the role of the FDXR-p73 loop in tumor suppression.