MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

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 r...

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Vydané v:Genes & development Ročník 34; číslo 7-8; s. 526
Hlavní autori: Venkatesh, Divya, O'Brien, Nicholas A, Zandkarimi, Fereshteh, Tong, David R, Stokes, Michael E, Dunn, Denise E, Kengmana, Everett S, Aron, Allegra T, Klein, Alyssa M, Csuka, Joleen M, Moon, Sung-Hwan, Conrad, Marcus, Chang, Christopher J, Lo, Donald C, D'Alessandro, Angelo, Prives, Carol, Stockwell, Brent R
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.04.2020
Predmet:
Animals
Brain - metabolism
Brain - physiopathology
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Ferroptosis - genetics
Glioblastoma - physiopathology
HCT116 Cells
Humans
Lipid Metabolism - genetics
Mutation
PPAR alpha - metabolism
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 - genetics
Proto-Oncogene Proteins c-mdm2 - metabolism
Rats
RNA Interference
Tumor Suppressor Protein p53 - metabolism
Ubiquinone - analogs & derivatives
Ubiquinone - metabolism
ferroptosis
MDMX
CoQ10
lipid metabolism
p53-independent
MDM2
cancer
PPARα
FSP1
ISSN:1549-5477, 1549-5477
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Shrnutí: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 , 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 PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα 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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1549-5477
1549-5477
DOI:10.1101/gad.334219.119