MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling.
Animals
Brain
/ metabolism
Cell Cycle Proteins
/ genetics
Ferroptosis
/ genetics
Glioblastoma
/ physiopathology
HCT116 Cells
Humans
Lipid Metabolism
/ genetics
Mutation
PPAR alpha
/ metabolism
Proto-Oncogene Proteins
/ genetics
Proto-Oncogene Proteins c-mdm2
/ antagonists & inhibitors
RNA Interference
Rats
Tumor Suppressor Protein p53
/ metabolism
Ubiquinone
/ analogs & derivatives
CoQ10
FSP1
MDM2
MDMX
PPARα
cancer
ferroptosis
lipid metabolism
p53-independent
Journal
Genes & development
ISSN: 1549-5477
Titre abrégé: Genes Dev
Pays: United States
ID NLM: 8711660
Informations de publication
Date de publication:
01 04 2020
01 04 2020
Historique:
received:
25
10
2019
accepted:
21
01
2020
pubmed:
23
2
2020
medline:
18
7
2020
entrez:
22
2
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 32079652
pii: gad.334219.119
doi: 10.1101/gad.334219.119
pmc: PMC7111265
doi:
Substances chimiques
Cell Cycle Proteins
0
MDM4 protein, human
0
PPAR alpha
0
Proto-Oncogene Proteins
0
Tumor Suppressor Protein p53
0
Ubiquinone
1339-63-5
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
coenzyme Q10
EJ27X76M46
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
526-543Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL146442
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220526
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA209896
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM066698
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA087497
Pays : United States
Organisme : NINDS NIH HHS
ID : R61 NS109407
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148151
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM079465
Pays : United States
Informations de copyright
© 2020 Venkatesh et al.; Published by Cold Spring Harbor Laboratory Press.
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