This Article Full Text Full Text (PDF) Supplemental Gene Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tung, L. Articles by Horwitz, K. B. Search for Related Content PubMed PubMed Citation Articles by Tung, L. Articles by Horwitz, K. B.

Progesterone Receptors (PR)-B and -A Regulate Transcription by Different Mechanisms: AF-3 Exerts Regulatory Control over Coactivator Binding to PR-B

Division of Endocrinology, Department of Medicine, University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado 80045

Address all correspondence and requests for reprints to: Hany Abdel-Hafiz, Department of Medicine, RC1 South, 12801 East 17th Avenue, P.O. Box 6511, Aurora, Colorado 80045. E-mail: hany.abdel-hafiz{at}uchsc.edu.

The two, nearly identical, isoforms of human progesterone receptors (PR), PR-B and -A, share activation functions (AF) 1 and 2, yet they possess markedly different transcriptional profiles, with PR-B being much stronger transactivators. Their differences map to a unique AF3 in the B-upstream segment (BUS), at the far N terminus of PR-B, which is missing in PR-A. Combined mutation of two LXXLL motifs plus tryptophan 140 in BUS, to yield PR-BdL140, completely destroys PR-B activity, because strong AF3 synergism with downstream AF1 and AF2 is eliminated. This synergism involves cooperative interactions among receptor multimers bound at tandem hormone response elements and is transferable to AFs of other nuclear receptors. Other PR-B functions—N-/C-terminal interactions, steroid receptor coactivator-1 coactivation, ligand-dependent down-regulation—also require an intact BUS. All three are autonomous in PR-A, and map to N-terminal regions common to both PR. This suggests that the N-terminal structure adopted by the two PR is different, and that for PR-B, this is controlled by BUS. Indeed, gene expression profiling of breast cancer cells stably expressing PR-B, PR-BdL140, or PR-A shows that mutation of AF3 destroys PR-B-dependent gene transcription without converting PR-B into PR-A. In sum, AF3 in BUS plays a critical modulatory role in PR-B, and in doing so, defines a mechanism for PR-B function that is fundamentally distinct from that of PR-A.

NURSA Molecule Pages Link:

Nuclear Receptors:   PR  |  AR

Coregulators:   SRC-1

Ligands:   17β-Estradiol  |  Dihydrotestosterone  |  Progesterone  |  R5020

This article has been cited by other articles:

				I. Quiles, L. Millan-Arino, A. Subtil-Rodriguez, B. Minana, N. Spinedi, C. Ballare, M. Beato, and A. Jordan Mutational Analysis of Progesterone Receptor Functional Domains in Stable Cell Lines Delineates Sets of Genes Regulated by Different Mechanisms Mol. Endocrinol., June 1, 2009; 23(6): 809 - 826. [Abstract] [Full Text] [PDF]

				H. Abdel-Hafiz, M. L. Dudevoir, and K. B. Horwitz Mechanisms Underlying the Control of Progesterone Receptor Transcriptional Activity by SUMOylation J. Biol. Chem., April 3, 2009; 284(14): 9099 - 9108. [Abstract] [Full Text] [PDF]

				F. De Amicis, S. Zupo, M. L. Panno, R. Malivindi, F. Giordano, I. Barone, L. Mauro, S. A. W. Fuqua, and S. Ando Progesterone Receptor B Recruits a Repressor Complex to a Half-PRE Site of the Estrogen Receptor {alpha} Gene Promoter Mol. Endocrinol., April 1, 2009; 23(4): 454 - 465. [Abstract] [Full Text] [PDF]

				M. D. Aupperlee, A. A. Drolet, S. Durairaj, W. Wang, R. C. Schwartz, and S. Z. Haslam Strain-Specific Differences in the Mechanisms of Progesterone Regulation of Murine Mammary Gland Development Endocrinology, March 1, 2009; 150(3): 1485 - 1494. [Abstract] [Full Text] [PDF]

				S. D. Conzen Minireview: Nuclear Receptors and Breast Cancer Mol. Endocrinol., October 1, 2008; 22(10): 2215 - 2228. [Abstract] [Full Text] [PDF]

				H. A. Molenda-Figueira, S. D. Murphy, K. L. Shea, N. K. Siegal, Y. Zhao, J. G. Chadwick Jr., L. A. Denner, and M. J. Tetel Steroid Receptor Coactivator-1 from Brain Physically Interacts Differentially with Steroid Receptor Subtypes Endocrinology, October 1, 2008; 149(10): 5272 - 5279. [Abstract] [Full Text] [PDF]

				Y. H. Ibrahim, S. A. Byron, X. Cui, A. V. Lee, and D. Yee Progesterone Receptor-B Regulation of Insulin-Like Growth Factor-Stimulated Cell Migration in Breast Cancer Cells via Insulin Receptor Substrate-2 Mol. Cancer Res., September 1, 2008; 6(9): 1491 - 1498. [Abstract] [Full Text] [PDF]

				A. Subtil-Rodriguez, L. Millan-Arino, I. Quiles, C. Ballare, M. Beato, and A. Jordan Progesterone Induction of the 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Promoter in Breast Cancer Cells Involves Coordinated Recruitment of STAT5A and Progesterone Receptor to a Distal Enhancer and Polymerase Tracking Mol. Cell. Biol., June 1, 2008; 28(11): 3830 - 3849. [Abstract] [Full Text] [PDF]

				K. P. Madauss, E. T. Grygielko, S.-J. Deng, A. C. Sulpizio, T. B. Stanley, C. Wu, S. A. Short, S. K. Thompson, E. L. Stewart, N. J. Laping, et al. A Structural and in Vitro Characterization of Asoprisnil: A Selective Progesterone Receptor Modulator Mol. Endocrinol., May 1, 2007; 21(5): 1066 - 1081. [Abstract] [Full Text] [PDF]

				K. D. Connaghan-Jones, A. F. Heneghan, M. T. Miura, and D. L. Bain Thermodynamic analysis of progesterone receptor-promoter interactions reveals a molecular model for isoform-specific function PNAS, February 13, 2007; 104(7): 2187 - 2192. [Abstract] [Full Text] [PDF]