PMID- 28747430
OWN - NLM
STAT- MEDLINE
DCOM- 20180831
LR  - 20211025
IS  - 1549-5477 (Electronic)
IS  - 0890-9369 (Print)
IS  - 0890-9369 (Linking)
VI  - 31
IP  - 12
DP  - 2017 Jun 15
TI  - Ferredoxin reductase is critical for p53-dependent tumor suppression via iron 
      regulatory protein 2.
PG  - 1243-1256
LID - 10.1101/gad.299388.117 [doi]
AB  - 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.
CI  - (c) 2017 Zhang et al.; Published by Cold Spring Harbor Laboratory Press.
FAU - Zhang, Yanhong
AU  - Zhang Y
AD  - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, 
      University of California at Davis, Davis, California 95616, USA.
FAU - Qian, Yingjuan
AU  - Qian Y
AD  - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, 
      University of California at Davis, Davis, California 95616, USA.
AD  - College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210014, 
      China.
FAU - Zhang, Jin
AU  - Zhang J
AD  - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, 
      University of California at Davis, Davis, California 95616, USA.
FAU - Yan, Wensheng
AU  - Yan W
AD  - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, 
      University of California at Davis, Davis, California 95616, USA.
FAU - Jung, Yong-Sam
AU  - Jung YS
AD  - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, 
      University of California at Davis, Davis, California 95616, USA.
AD  - College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210014, 
      China.
FAU - Chen, Mingyi
AU  - Chen M
AD  - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, 
      Texas 75390, USA.
FAU - Huang, Eric
AU  - Huang E
AD  - Department of Pathology, School of Medicine, University of California at Davis 
      Health, Sacramento, California 95817, USA.
FAU - Lloyd, Kent
AU  - Lloyd K
AD  - Department of Surgery, School of Medicine, University of California at Davis 
      Health, Sacramento, California 95817, USA.
FAU - Duan, Yuyou
AU  - Duan Y
AD  - Department of Dermatology and Internal Medicine, University of California at 
      Davis Health, Sacramento, California 95616, USA.
FAU - Wang, Jian
AU  - Wang J
AD  - Department of Pathology, School of Medicine, Wayne State University, Detroit, 
      Michigan 48201 USA.
FAU - Liu, Gang
AU  - Liu G
AD  - Department of Medicine, School of Medicine, University of Alabama at Birmingham, 
      Birmingham, Alabama 35294, USA.
FAU - Chen, Xinbin
AU  - Chen X
AUID- ORCID: 0000-0002-4582-6506
AD  - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, 
      University of California at Davis, Davis, California 95616, USA.
LA  - eng
GR  - P30 CA093373/CA/NCI NIH HHS/United States
GR  - R01 CA195828/CA/NCI NIH HHS/United States
GR  - R01 CA076069/CA/NCI NIH HHS/United States
GR  - R29 CA076069/CA/NCI NIH HHS/United States
GR  - R01 CA224433/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20170726
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (Tumor Suppressor Protein p53)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.18.1.2 (Ferredoxin-NADP Reductase)
RN  - EC 4.2.1.3 (Iron Regulatory Protein 2)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Embryonic Development/genetics
MH  - Ferredoxin-NADP Reductase/genetics/*metabolism
MH  - Gene Expression Regulation/genetics
MH  - HCT116 Cells
MH  - Hep G2 Cells
MH  - Homeostasis/*genetics
MH  - Humans
MH  - Iron/metabolism
MH  - Iron Regulatory Protein 2/genetics/*metabolism
MH  - Liver Diseases/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neoplasms/genetics
MH  - Protein Biosynthesis
MH  - Tumor Suppressor Protein p53/genetics/*metabolism
PMC - PMC5558926
OTO - NOTNLM
OT  - FDX1
OT  - FDX2
OT  - FDXR
OT  - IRP2
OT  - iron homeostasis
OT  - mRNA translation
OT  - p53
EDAT- 2017/07/28 06:00
MHDA- 2018/09/01 06:00
PMCR- 2017/12/15
CRDT- 2017/07/28 06:00
PHST- 2017/03/24 00:00 [received]
PHST- 2017/06/26 00:00 [accepted]
PHST- 2017/07/28 06:00 [pubmed]
PHST- 2018/09/01 06:00 [medline]
PHST- 2017/07/28 06:00 [entrez]
PHST- 2017/12/15 00:00 [pmc-release]
AID - gad.299388.117 [pii]
AID - 10.1101/gad.299388.117 [doi]
PST - ppublish
SO  - Genes Dev. 2017 Jun 15;31(12):1243-1256. doi: 10.1101/gad.299388.117. Epub 2017 
      Jul 26.