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.

Public Health Relevance

The propose study is highly relevant to human health because this study will uncover a novel mechanism by which p53/p63/p73 are differentially regulated by FDXR and reveal a novel pathway for p53/p63/p73 in tumor suppression via FDXR.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA224433-02
Application #
9635755
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Watson, Joanna M
Project Start
2018-02-01
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Zhang, Jin; Chen, Xinbin (2018) p53 tumor suppressor and iron homeostasis. FEBS J :
Zhang, Yanhong; Qian, Yingjuan; Zhang, Jin et al. (2017) Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. Genes Dev 31:1243-1256