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Article
Progesterone regulation of activating protein-1 transcriptional activity: a possible mechanism of progesterone inhibition of endometrial cancer cell growth
The Journal of steroid biochemistry and molecular biology
  • Donghai Dai, University of Iowa
  • E. S. Litman
  • E. Schonteich
  • K. K. Leslie
Document Type
Article
Peer Reviewed
1
Publication Date
11-1-2003
NLM Title Abbreviation
J Steroid Biochem Mol Biol
PubMed ID
14672732
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.
Keywords
  • 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
Published Article/Book Citation
The Journal of steroid biochemistry and molecular biology, 87:2-3 (2003) pp.123-131.
Disciplines
Citation Information
Donghai Dai, E. S. Litman, E. Schonteich and K. K. Leslie. "Progesterone regulation of activating protein-1 transcriptional activity: a possible mechanism of progesterone inhibition of endometrial cancer cell growth" The Journal of steroid biochemistry and molecular biology Vol. 87 Iss. 2-3 (2003) p. 123 - 131 ISSN: 0960-0760
Available at: http://works.bepress.com/donghai_dai/21/