title: MAPK14 cooperates with MAPK3/1 to regulate endothelin-1-mediated prostaglandin synthase 2 induction and survival in leiomyoma but not in normal myometrial cells.
abstract: We recently reported that in ELT3 uterine leiomyoma cells, but not in normal myometrial cells, endothelin (ET)-1 exerts a survival effect insensitive to MAPK3/1(ERK1/2) inhibition. In the present work, we investigated the potential role of MAPK14 (p38) in this ET-1-mediated effect. We demonstrated that, in ELT3, but not in normal myometrial cells, ET-1 activated MAPK14. Data based on pharmacological and siRNA approaches indicate that ETA and ETB receptors contributed to the activation of MAPK14 by ET-1 through a mechanism involving Gi protein, but not PI3-kinase. The inhibition of MAPK3/1 by U0126 did not affect the activation of MAPK14 by ET-1. Conversely, the inhibition of MAPK14 by SB203580 and the down-regulation of MAP2K3/MAP2K6 (kinases upstream of MAPK14) by specific siRNA did not alter the activation of MAPK3/1. These data indicate that MAPK14 was activated by ET-1 independently from MAPK3/1. Furthermore, ET-1 increased protein expression of prostaglandin synthase 2 (PTGS2 or COX2), prostaglandin E2 (PGE2) production, and subsequent ELT3 cell survival. The inhibition of PTGS2 induction and subsequent survival induced by ET-1 required the coinhibition of MAPK14 and MAPK3/1. Our findings provide evidence that ET-1 activated MAPK14 only in ELT3 cells, but not in normal myometrial cells. This MAPK14 activation was required, in addition to MAPK3/1 in ET-1-mediated survival through the COX2/prostaglandin axis, and may explain the absence of ET-1 antiapoptotic effect in normal myometrial cells. Our data reinforce the role of ET-1 and associated signaling pathways in leiomyoma pathology.
authors.affiliation: Institut de Biochimie et Biophysique Moléculaire et Cellulaire, CNRS/UMR 8619, Université Paris-Sud 11, Orsay, France.
authors.forename: Clement
authors.initials: C
authors.lastname: Oyeniran
authors.forename: Zahra
authors.initials: Z
authors.lastname: Tanfin
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism / Q000502:physiology; D044023:Receptor, Endothelin B / Q000378:metabolism / Q000502:physiology; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D051546:Cyclooxygenase 2; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3