Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
06 01 2023
06 01 2023
Historique:
entrez:
6
1
2023
pubmed:
7
1
2023
medline:
11
1
2023
Statut:
ppublish
Résumé
Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of
Identifiants
pubmed: 36608116
doi: 10.1126/sciadv.ade1694
pmc: PMC9821870
doi:
Substances chimiques
polyglutamine
26700-71-0
Receptors, Androgen
0
Calcium
SY7Q814VUP
Cyclin-Dependent Kinases
EC 2.7.11.22
Phosphoric Monoester Hydrolases
EC 3.1.3.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
eade1694Subventions
Organisme : NINDS NIH HHS
ID : R01 NS100023
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS122140
Pays : United States
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