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p38 and p42/44 MAPKs Differentially Regulate Progesterone Receptor A and B Isoform Stabilization.: Distinct MAPKs regulate PRA and PRB stability

Abstract : 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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https://www.hal.inserm.fr/inserm-00611160
Contributor : Marc Lombes <>
Submitted on : Saturday, August 4, 2012 - 7:00:03 AM
Last modification on : Wednesday, September 16, 2020 - 4:52:18 PM
Long-term archiving on: : Tuesday, December 13, 2016 - 6:48:55 PM

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Junaid Ali Khan, Larbi Amazit, Catherine Bellance, Anne Guiochon-Mantel, Marc Lombes, et al.. p38 and p42/44 MAPKs Differentially Regulate Progesterone Receptor A and B Isoform Stabilization.: Distinct MAPKs regulate PRA and PRB stability. Mol Endocrinol, 2011, 25 (10), pp.1710-24. ⟨10.1210/me.2011-1042⟩. ⟨inserm-00611160⟩

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