title: p38 and p42/44 MAPKs differentially regulate progesterone receptor A and B isoform stabilization.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 693, Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Junaid A
authors.initials: JA
authors.lastname: Khan
authors.forename: Larbi
authors.initials: L
authors.lastname: Amazit
authors.forename: Catherine
authors.initials: C
authors.lastname: Bellance
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.forename: Hugues
authors.initials: H
authors.lastname: Loosfelt
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000473:pathology; D005260:Female; D006067:Gonanes / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011397:Promegestone / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D006067:Gonanes; D008024:Ligands; D020033:Protein Isoforms; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D010768:Phosphoserine; D015735:Mifepristone; D011397:Promegestone; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D046988:Proteasome Endopeptidase Complex; C053238:onapristone