p90RSK Regulates p53 Pathway by MDM2 Phosphorylation in Thyroid Tumors.
MDM2
apoptosis
cancer
cell proliferation
p53
p90RSK
proteasome degradation
targeted therapy
tumorigenesis
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
25 Dec 2022
25 Dec 2022
Historique:
received:
14
10
2022
revised:
10
12
2022
accepted:
21
12
2022
entrez:
8
1
2023
pubmed:
9
1
2023
medline:
9
1
2023
Statut:
epublish
Résumé
The expression level of the tumor suppressor p53 is controlled by the E3 ubiquitin ligase MDM2 with a regulatory feedback loop, which allows p53 to upregulate its inhibitor MDM2. In this manuscript we demonstrated that p90RSK binds and phosphorylates MDM2 on serine 166 both in vitro and in vivo by kinase assay, immunoblot, and co-immunoprecipitation assay; this phosphorylation increases the stability of MDM2 which in turn binds p53, ubiquitinating it and promoting its degradation by proteasome. A pharmacological inhibitor of p90RSK, BI-D1870, decreases MDM2 phosphorylation, and restores p53 function, which in turn transcriptionally increases the expression of cell cycle inhibitor p21 and of pro-apoptotic protein Bax and downregulates the anti-apoptotic protein Bcl-2, causing a block of cell proliferation, measured by a BrdU assay and growth curve, and promoting apoptosis, measured by a TUNEL assay. Finally, an immunohistochemistry evaluation of primary thyroid tumors, in which p90RSK is very active, confirms MDM2 stabilization mediated by p90RSK phosphorylation.
Identifiants
pubmed: 36612117
pii: cancers15010121
doi: 10.3390/cancers15010121
pmc: PMC9817759
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : POR FESR 2014-2020 Technology Platform -Fight Against Oncological Pathologies-
ID : Project CUP: B61C17000070007
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