title: The requirement for p42/p44 MAPK activity in progesterone receptor-mediated gene regulation is target gene-specific.
abstract: Recent studies have suggested that progestins play a role in the etiology of breast cancer; however, the mechanisms by which progestins promote tumor formation/progression have not been defined. Progestin action, in target tissues such as the breast, is mediated by the progesterone receptor (PR). PR signaling is complex and PR regulates transcription of target genes through a variety of mechanisms. Many cell signaling pathways are activated inappropriately in breast cancer cells and these pathways can regulate PR activity. For example, the p42/p44 MAPK pathway can regulate PR function by altering phosphorylation of PR, as well as its coregulators. We found that inhibition of the p42/p44 MAPK signaling pathway with a MEK inhibitor (U0126) impairs PR-mediated gene induction, but not gene repression. In addition, the effects of U0126 on PR-mediated gene transcription are much greater with long-term versus short-term inhibition and are gene-specific. Finally, treatment with U0126 delays phosphorylation of Ser294, but does not block phosphorylation completely, suggesting that p42/p44 MAPK kinase is not the dominant kinase responsible for phosphorylating this site. Collectively, these studies suggest that in addition to the p42/p44 MAPK pathway, other signaling pathways are also important for PR transcriptional activity in breast cancer cells. The integration of PR transcriptional effects and cell signaling pathways has implications for the initiation or progression of breast cancer. Understanding how these pathways interact may aid in the development of prevention and/or treatment strategies for the disease.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, M515, One Baylor Plaza, Houston, TX 77030, USA.
authors: Lindsey S
authors: LS
authors: Treviño
authors: William E
authors: WE
authors: Bingman
authors: Dean P
authors: DP
authors: Edwards
authors: Weigel
authors: W
authors: Nl
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002070:Butadienes / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D011980:Receptors, Progesterone / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D002070:Butadienes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011980:Receptors, Progesterone; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
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