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.

项目摘要 p53肿瘤抑制剂家族由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器。我们和其他人表明 p53，p63和p73直接诱导那种铁氧还蛋白还原酶（FDXR）。初步调查 表明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p53依赖性凋亡的敏感性 方式。为了研究FDXR的生物学功能，我们通过 生成FDXR缺陷的细胞和小鼠模型。我们证明了FDXR缺乏 促进铁调节蛋白2（IRP2）表达。我们还表明细胞缺乏 FDXR在线粒体中表现出铁超负荷。最有趣的是，我们表明细胞 FDXR缺乏也缺乏p53和p73表达。相反，p63表达为 FDXR缺陷型细胞中的增加。此外，FDXR +/-小鼠的寿命很短 自发肿瘤的高发病率。这些观察结果促使我们假设 FDXR-P53家庭途径对于抑制肿瘤是必需的。为了测试这一点，我们将确定： （1）p53如何受FDXR的调节以及FDXR-P53环在肿瘤抑制中的作用； （2） p63如何受FDXR的调节以及FDXR-P63环在肿瘤抑制中的作用； （3） P73如何受FDXR的调节以及FDXR-P73环在肿瘤抑制中的作用。