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Venkatesh, D.* ; O'Brien, N.A.* ; Zandkarimi, F.* ; Tong, D.R.* ; Stokes, M.E.* ; Dunn, D.E.* ; Kengmana, E.S.* ; Aron, A.T.* ; Klein, A.M.* ; Csuka, J.M.* ; Moon, S.H.* ; Conrad, M. ; Chang, C.J.* ; Lo, D.C.* ; D'Alessandro, A.* ; Prives, C.* ; Stockwell, B.R.*

MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling.

Genes Dev. 34, 526-543 (2020)
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MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q(10), an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPAR alpha activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPAR alpha activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Ferroptosis ; Mdm2 ; Mdmx ; P53-independent ; Ppar Alpha ; Lipid Metabolism ; Fsp1 ; Coq(10) ; Cancer; Proliferator-activated Receptor; Cell-death; P53; Metabolism; Inhibitors; Identification; Oxidation; Apoptosis; Complex; Target
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0890-9369
e-ISSN 1549-5477
Journal Genes and Development
Quellenangaben Volume: 34, Issue: 7-8, Pages: 526-543 Article Number: , Supplement: ,
Publisher Cold Spring Harbor Laboratory Press
Publishing Place 1 Bungtown Rd, Cold Spring Harbor, Ny 11724 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506900-001
DOI 10.1101/gad.334219.119
WOS ID WOS:000522794600006
Scopus ID 85082779956
Erfassungsdatum 2020-04-20
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