Progesterone regulation of activating protein-1 transcriptional activity: a possible mechanism of progesterone inhibition of endometrial cancer cell growth
Journal, Book or Conference Title
The Journal of steroid biochemistry and molecular biology
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.
Cell Division/drug effects, Cell Line, Tumor, Cyclin D1/biosynthesis/genetics, DNA/metabolism, Endometrial Neoplasms/drug therapy/pathology, Female, Humans, Progesterone/pharmacology, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun/metabolism/pharmacology, RNA, Messenger/biosynthesis, Receptors, Progesterone/genetics/metabolism, Transcription Factor AP-1/antagonists & inhibitors/physiology, Transcription, Genetic/drug effects, Tumor Suppressor Protein p53/biosynthesis/genetics, rho GTP-Binding Proteins/biosynthesis/genetics
NLM Title Abbreviation
J Steroid Biochem Mol Biol
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