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

铁氧还蛋白还原酶和 p53 家族在肿瘤抑制中的反馈回路

• 批准号: 10330451
• 负责人: Xinbin Chen
• 金额: $ 38.36万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330451
• 关键词: Apoptosis; Biochemical; Biogenesis; Biological Process; Biological Testing; Cell model; Cells; Cytochrome P450; DNA Damage; Ectopic Expression; Electron Transport; Embryo; Exhibits; Family; Family member; Feedback; Ferredoxin; Genes; Genetic Transcription; Genetic Translation; Health; Heterozygote; Human; Incidence; Investigation; Iron; Iron Overload; Iron Regulatory Protein 2; Knockout Mice; Longevity; Mediating; Mitochondria; Mus; NADP; Oxidoreductase; Pathway interactions; Pilot Projects; Play; Protein Family; Radiation therapy; Regulation; Role; Steroid biosynthesis; Sulfur; TP53 gene; Testing; Tumor Suppression; Tumor Suppressor Proteins; biodosimetry; in utero; iron metabolism; mRNA Stability; mouse model; mutant; neoplastic cell; novel; peripheral blood; tumor; tumorigenesis

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.

项目概要 p53 肿瘤抑制因子家族由 p53、p63 和 p73 组成。 p53 家族蛋白 主要通过其转录靶标充当肿瘤抑制因子。我们和其他人展示了 铁氧还蛋白还原酶 (FDXR) 直接由 p53、p63 和 p73 诱导。初步调查 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 p53 依赖性 DNA 损伤诱导的细胞凋亡的敏感性 方式。为了研究 FDXR 的生物学功能，我们进行了一项初步研究： 生成 FDXR 缺陷细胞和小鼠模型。我们证明了 FDXR 缺陷 促进铁调节蛋白 2 (IRP2) 的表达。我们还表明，细胞缺乏 FDXR 在线粒体中表现出铁过载。最有趣的是，我们发现细胞 FDXR 缺陷也导致 p53 和 p73 表达缺陷。相比之下，p63 表达为 FDXR 缺陷细胞中增加。此外，FDXR+/- 小鼠的寿命很短 自发性肿瘤发生率高。这些观察结果促使我们假设 FDXR-p53 家族通路对于肿瘤抑制是必需的。为了测试这一点，我们将确定： (1) FDXR如何调控p53以及FDXR-p53环在肿瘤抑制中的作用； (2) FDXR 如何调节 p63 以及 FDXR-p63 环在肿瘤抑制中的作用； (3) FDXR 如何调节 p73 以及 FDXR-p73 环在肿瘤抑制中的作用。