PMID: identifiant
de la référence Pubmed : |
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 (21816898)  |
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| titre : |
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p38 and p42/44 MAPKs Differentially Regulate Progesterone Receptor A and B Isoform Stabilization. |
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| auteur(s) : |
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Junaid Ali Khan1, Larbi Amazit1, Catherine Bellance1, Anne Guiochon-Mantel1, 2, Marc Lombes1, 3, Hugues Loosfelt ( ) 1 |
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| laboratoire : |
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| titre abrégé : |
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Distinct MAPKs regulate PRA and PRB stability |
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| résumé : |
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Progesterone receptor (PR) isoforms (PRA and PRB) are implicated in the progression of breast cancers frequently associated with imbalanced PRA/PRB expression ratio. Antiprogestins represent potential antitumorigenic agents for such hormone-dependent cancers. To investigate the mechanism(s) controlling PR isoforms degradation/stability in the context of agonist and antagonist ligands, we used endometrial and mammary cancer cells stably expressing PRA and/or PRB. We found that the antiprogestin RU486 inhibited the agonist-induced turnover of PR isoforms through active mechanism(s) involving distinct MAPK-dependent phosphorylations. p42/44 MAPK activity inhibited proteasome-mediated degradation of RU486-bound PRB but not PRA in both cell lines. Ligand-induced PRB turnover required neosynthesis of a mandatory down-regulating partner whose interaction/function is negatively controlled by p42/44 MAPK. Such regulation strongly influenced expression of various endogenous PRB target genes in a selective manner, supporting functional relevance of the mechanism. Interestingly, in contrast to PRB, PRA stability was specifically increased by MAPK kinase kinase 1-induced p38 MAPK activation. Selective inhibition of p42/p44 or p38 activity resulted in opposite variations of the PRA/PRB expression ratio. Moreover, MAPK-dependent PR isoforms stability was independent of PR serine-294 phosphorylation previously proposed as a major sensor of PR down-regulation. In sum, we demonstrate that MAPK-mediated cell signaling differentially controls PRA/PRB expression ratio at posttranslational level through ligand-sensitive processes. Imbalance in PRA/PRB ratio frequently associated with carcinogenesis might be a direct consequence of disorders in MAPK signaling that might switch cellular responses to hormonal stimuli and contribute towards pathogenesis. |
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| domaine : |
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Sciences du Vivant/Médecine humaine et pathologie/Endocrinologie et métabolisme
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langue du texte
intégral : |
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Anglais |
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| ISSN : |
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1944-9917 |
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| type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1210/me.2011-1042 |
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| journal : |
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Mol Endocrinol |
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| Audience : |
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internationale |
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| date de publication : |
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10/2011 |
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date de publication
électronique : |
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04/08/2011 |
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| volume : |
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25 |
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| numéro : |
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10 |
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| page, identifiant, ... : |
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1710-24 |
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| mots-clés auteur : |
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Steroid hormone receptor – antiprogestins – phosphorylation – turnover – proteasome – MAP kinases – transcription |
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