PMID- 32304229 OWN - NLM STAT- MEDLINE DCOM- 20201116 LR - 20210212 IS - 1096-9896 (Electronic) IS - 0022-3417 (Print) IS - 0022-3417 (Linking) VI - 251 IP - 3 DP - 2020 Jul TI - FDXR regulates TP73 tumor suppressor via IRP2 to modulate aging and tumor suppression. PG - 284-296 LID - 10.1002/path.5451 [doi] AB - Ferredoxin reductase (FDXR) is a mitochondrial flavoprotein that initiates electron transport from NADPH to several cytochromes P450 via two electron carriers, ferredoxin 1 (FDX1) and FDX2. FDXR is the sole ferredoxin reductase in humans and plays a critical role in steroidogenesis and biosynthesis of heme and iron-sulfur clusters. However, much less is known about the role of FDXR in cancer. Here, we show that FDXR plays a role in tumorigenesis by modulating expression of the tumor suppressor p73. By using genetically modified mouse models, we recently showed that mice deficient in either Fdxr or Trp73 had a shorter lifespan and were prone to spontaneous tumors as compared with wild-type (WT) mice. Interestingly, compound Trp73 (+/-) ;Fdxr (+/-) mice lived longer and developed fewer tumors when compared with Fdxr (+/-) or Trp73 (+/-) mice. Moreover, we found that cellular senescence was increased in Trp73 (+/-) and Fdxr (+/-) mouse embryonic fibroblasts (MEFs), which was further increased in Trp73 (+/-) ;Fdxr (+/-) MEFs, as compared with that in WT MEFs. As FDXR is regulated by p73, we examined whether there was a feedback regulation between p73 and FDXR. Indeed, we found that Trp73 expression was decreased by loss of Fdxr in MEFs and that FDXR is required for p73 expression in multiple human cancer cell lines independent of p53. Mechanistically, we found that loss of FDXR, via FDX2, increased expression of iron-binding protein 2 (IRP2), which subsequently repressed TP73 mRNA stability. We also showed that TP73 transcript contained an iron response element in its 3'UTR, which was required for IRP2 to destabilize TP73 mRNA. Together, these data reveal a novel regulation of p73 by FDXR via IRP2 and that the FDXR-p73 axis plays a critical role in aging and tumor suppression. (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. CI - (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. FAU - Zhang, Jin AU - Zhang J AD - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, USA. FAU - Kong, Xiangmudong AU - Kong X AD - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, USA. FAU - Zhang, Yanhong AU - Zhang Y AD - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, USA. FAU - Sun, Wenqiang AU - Sun W AD - Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, USA. FAU - Wang, Jian AU - Wang J AUID- ORCID: 0000-0003-4503-5058 AD - School of Medicine, Wayne State University, Detroit, MI, USA. FAU - Chen, Mingyi AU - Chen M AD - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 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, CA, USA. LA - eng GR - 2018-18F/CCAH Grant/International GR - P30 CA093373/CA/NCI NIH HHS/United States GR - R01 CA081237/CA/NCI NIH HHS/United States GR - CA081237/CA/NCI NIH HHS/United States GR - R01 CA224433/CA/NCI NIH HHS/United States GR - CA224433/CA/NCI NIH HHS/United States GR - CA081237/CA/NCI NIH HHS/United States GR - CA224433/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200518 PL - England TA - J Pathol JT - The Journal of pathology JID - 0204634 RN - 0 (RNA, Messenger) RN - 0 (RNA, Neoplasm) RN - 0 (TP73 protein, human) RN - 0 (Trp73 protein, mouse) RN - 0 (Tumor Protein p73) RN - E1UOL152H7 (Iron) RN - EC 1.18.1.2 (Ferredoxin-NADP Reductase) RN - EC 4.2.1.3 (IREB2 protein, human) RN - EC 4.2.1.3 (Ireb2 protein, mouse) RN - EC 4.2.1.3 (Iron Regulatory Protein 2) SB - IM MH - Animals MH - *Cell Proliferation MH - *Cellular Senescence MH - Ferredoxin-NADP Reductase/deficiency/genetics/*metabolism MH - Gene Expression Regulation, Neoplastic MH - HCT116 Cells MH - Humans MH - Iron/metabolism MH - Iron Regulatory Protein 2/genetics/*metabolism MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neoplasms/*enzymology/genetics/pathology MH - RNA Stability MH - RNA, Messenger/genetics/metabolism MH - RNA, Neoplasm/genetics/metabolism MH - Signal Transduction MH - Tumor Burden MH - Tumor Protein p73/deficiency/genetics/*metabolism PMC - PMC7748393 MID - NIHMS1652997 OTO - NOTNLM OT - FDX1 OT - FDX2 OT - iron metabolism OT - iron response element OT - mRNA stability COIS- No conflicts of interest were declared. EDAT- 2020/04/19 06:00 MHDA- 2020/11/18 06:00 PMCR- 2020/12/18 CRDT- 2020/04/19 06:00 PHST- 2019/10/25 00:00 [received] PHST- 2020/02/27 00:00 [revised] PHST- 2020/04/03 00:00 [accepted] PHST- 2020/04/19 06:00 [pubmed] PHST- 2020/11/18 06:00 [medline] PHST- 2020/04/19 06:00 [entrez] PHST- 2020/12/18 00:00 [pmc-release] AID - 10.1002/path.5451 [doi] PST - ppublish SO - J Pathol. 2020 Jul;251(3):284-296. doi: 10.1002/path.5451. Epub 2020 May 18.