Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2

Yanhong Zhang, Yingjuan Qian, Jin Zhang, Wensheng Yan, Yong Sam Jung, Mingyi Chen, Eric C Huang, Kevin C K Lloyd, YuYou Duan, Jian Wang, Gang Liu, Xinbin Chen

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Ferredoxin reductase (FDXR), a target of p53, modulates p53-dependent apoptosis and is necessary for steroidogenesis and biogenesis of iron-sulfur clusters. To determine the biological function of FDXR, we generated a Fdxr-deficient mouse model and found that loss of Fdxr led to embryonic lethality potentially due to iron overload in developing embryos. Interestingly, mice heterozygous in Fdxr had a short life span and were prone to spontaneous tumors and liver abnormalities, including steatosis, hepatitis, and hepatocellular carcinoma. We also found that FDXR was necessary for mitochondrial iron homeostasis and proper expression of several master regulators of iron metabolism, including iron regulatory protein 2 (IRP2). Surprisingly, we found that p53 mRNA translation was suppressed by FDXR deficiency via IRP2. Moreover, we found that the signal from FDXR to iron homeostasis and the p53 pathway was transduced by ferredoxin 2, a substrate of FDXR. Finally, we found that p53 played a role in iron homeostasis and was required for FDXR-mediated iron metabolism. Together, we conclude that FDXR and p53 are mutually regulated and that the FDXR-p53 loop is critical for tumor suppression via iron homeostasis.

Original languageEnglish (US)
Pages (from-to)1243-1256
Number of pages14
JournalGenes and Development
Volume31
Issue number12
DOIs
StatePublished - Jun 15 2017

Fingerprint

Iron Regulatory Protein 2
Ferredoxins
Oxidoreductases
Neoplasms
Iron
Homeostasis
Iron Overload
Protein Biosynthesis
Sulfur
Hepatitis

Keywords

  • FDX1
  • FDX2
  • FDXR
  • Iron homeostasis
  • IRP2
  • mRNA translation
  • p53

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. / Zhang, Yanhong; Qian, Yingjuan; Zhang, Jin; Yan, Wensheng; Jung, Yong Sam; Chen, Mingyi; Huang, Eric C; Lloyd, Kevin C K; Duan, YuYou; Wang, Jian; Liu, Gang; Chen, Xinbin.

In: Genes and Development, Vol. 31, No. 12, 15.06.2017, p. 1243-1256.

Research output: Contribution to journalArticle

Zhang, Yanhong ; Qian, Yingjuan ; Zhang, Jin ; Yan, Wensheng ; Jung, Yong Sam ; Chen, Mingyi ; Huang, Eric C ; Lloyd, Kevin C K ; Duan, YuYou ; Wang, Jian ; Liu, Gang ; Chen, Xinbin. / Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. In: Genes and Development. 2017 ; Vol. 31, No. 12. pp. 1243-1256.
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