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p38 and p42/44 MAPKs differentially regulate progesterone receptor A and B isoform stabilization.
- Source :
-
Molecular endocrinology (Baltimore, Md.) [Mol Endocrinol] 2011 Oct; Vol. 25 (10), pp. 1710-24. Date of Electronic Publication: 2011 Aug 04. - Publication Year :
- 2011
-
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.
- Subjects :
- Breast Neoplasms enzymology
Breast Neoplasms pathology
Cell Line, Tumor
Endometrial Neoplasms enzymology
Endometrial Neoplasms pathology
Female
Gonanes pharmacology
Humans
Ligands
MAP Kinase Kinase Kinase 1 metabolism
Mifepristone pharmacology
Models, Biological
Phosphorylation drug effects
Phosphoserine metabolism
Promegestone pharmacology
Proteasome Endopeptidase Complex metabolism
Protein Isoforms agonists
Protein Isoforms antagonists & inhibitors
Protein Isoforms metabolism
Protein Stability drug effects
Receptors, Progesterone agonists
Receptors, Progesterone antagonists & inhibitors
Transcription, Genetic drug effects
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 metabolism
Receptors, Progesterone metabolism
p38 Mitogen-Activated Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1944-9917
- Volume :
- 25
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular endocrinology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 21816898
- Full Text :
- https://doi.org/10.1210/me.2011-1042