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

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
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-02-01 至 2024-01-31

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中文摘要
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英文摘要
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.
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会议论文
The Mechanism and Therapeutic Potential of Targeting the Ninjurin Pathway for Tumors Carrying Wild-Type p53
The Mechanism and Therapeutic Potential of Targeting the Ninjurin Pathway for Tumors Carrying Wild-Type p53
UC Davis DVM/PhD Medical Scientist Training Program
Mechanism of p53-dependent Tumor Suppression
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