title: Progesterone regulation of activating protein-1 transcriptional activity: a possible mechanism of progesterone inhibition of endometrial cancer cell growth.
abstract: The uterine endometrium and cancers derived from it are classic models of hormone action: estrogen promotes growth and progesterone inhibits proliferation and results in differentiation. We have now identified a major pathway through which progesterone causes these growth-limiting effects. Ligand-bound progesterone receptors modulate the composition and transcriptional activity of members of the activating protein-1 (AP-1) family, and in particular, c-Jun. First, a dominant negative form of c-Jun inhibits the constitutive growth of Hec50co cells in a manner similar to the effects of progesterone through progesterone B receptors. Second, progesterone inhibits the transcriptional activity of the AP-1 complex in reporter gene assays. Third, the DNA binding of AP-1 and the composition of the individual AP-1 factors on DNA is regulated by progesterone on electrophoretic mobility shift assays. Fourth, progesterone strongly inhibits total AP-1 as well as c-Jun recruitment to the cyclin D1 promoter, but enhances AP-1 occupancy on the p53 and p21 promoters, as shown by chromatin immunoprecipitation assays. The effects of progesterone on AP-1 DNA binding are confirmed to result in altered transcription of these AP-1 target genes by RT-PCR. These studies establish that modulation of AP-1 activity is a potential pathway of progesterone-induced growth inhibition in endometrial cancer cells.
authors.affiliation: Reproductive Molecular Biology Laboratory, The Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-5286, USA. ddai@salud.unm.edu
authors.forename: Donghai
authors.initials: D
authors.lastname: Dai
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Litman
authors.forename: Eric
authors.initials: E
authors.lastname: Schonteich
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
mesh_terms: D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D006801:Humans; D011374:Progesterone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; C101118:progesterone receptor A; C097314:progesterone receptor B; D019938:Cyclin D1; D011374:Progesterone; D004247:DNA; D020741:rho GTP-Binding Proteins