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Title: | Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function |
Author: | Piol, Diana Tosatto, Laura Zuccaro, Emanuela Anderson, Eric N. Falconieri, Antonella Polanco, María J. Marchioretti, Caterina Lia, Federica White, Joseph Bregolin, Elisa Minervini, Giovanni Parodi, Sara Salvatella i Giralt, Xavier Arrigoni, Giorgio Ballabio, Andrea Spada, Albert R. la Tosatto, Silvio C. E. Sambataro, Fabio Medina, Diego L. Pandey, Udal B. Basso, Manuela Pennuto, Maria |
Keywords: | Atròfia muscular Receptors cel·lulars Muscular atrophy Cell receptors |
Issue Date: | 6-Jan-2023 |
Publisher: | American Association for the Advancement of Science |
Abstract: | 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 Myc and other genes involved in DNA damage, senescence, and apoptosis, indicating that the cell cycle-regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells. |
Note: | Reproducció del document publicat a: https://doi.org/10.1126/sciadv.ade1694 |
It is part of: | Science Advances, 2023, vol. 9, num. 1 |
URI: | http://hdl.handle.net/2445/200285 |
Related resource: | https://doi.org/10.1126/sciadv.ade1694 |
ISSN: | 2375-2548 |
Appears in Collections: | Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona)) |
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Piol_Salvatella_et al_sciadv_2023.pdf | 2.73 MB | Adobe PDF | View/Open |
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