Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors [published erratum appears in Mol Endocrinol 1993 Nov;7(11):1378]

doi:10.1210/me.7.10.1256

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Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors [published erratum appears in Mol Endocrinol 1993 Nov;7(11):1378]

L Tung, MK Mohamed, JP Hoeffler, GS Takimoto and KB Horwitz
Department of Medicine, University of Colorado Health Sciences Center Denver 80262.

When antagonist-occupied steroid receptors have agonist-like effects, the clinical consequences are grave. We present evidence that human progesterone B-receptors (hPRB) when occupied by progesterone antagonists, inappropriately activate transcription by an unusual mechanism that does not require the canonical progesterone response element (PRE). In HeLa cells cotransfected with a PRE-tk- chloramphenicol acetyltransferase reporter and a hPRB expression vector, strong transcription is seen not only when receptors are activated by the agonist R5020, but also in the presence of the three antiprogestins, RU486, ZK112993, and ZK98299. Human PRB occupied by ZK98299 do not bind to a PRE, suggesting that the transcriptional stimulation is independent of DNA binding. Indeed, a tk-chloramphenicol acetyltransferase promoter-reporter lacking the PRE loses transcriptional activation by the agonist, but retains transactivation by the three antagonists. The PRE-independent antagonist-induced transcription requires that hPRB have an intact DNA-binding domain, but hPR target gene specificity is not required, because a hPRB mutant that binds an estrogen response element still activates transcription. It appears that antagonist-occupied hPR activate transcription without binding to a PRE, perhaps by interacting with tethering proteins instead. Even a gene that is not a normal progesterone target could be aberrantly activated. Human cells contain equimolar amounts of hPRB and the N-terminally truncated natural isotype, hPRA. Unlike hPRB, hPRA are not transcriptionally activated by progesterone antagonists. We, therefore, tested the effects of antagonists when the two receptor isotypes are coexpressed and found that A-receptors can annul the inappropriate transcription by B-receptors. Thus, when both receptor forms are present, the hPRA phenotype is dominant. Moreover, pure hPRB/hPRA heterodimers, produced by fos/jun leucine zipper domain-hPR chimeras, also have the inactive transcriptional phenotype of hPRA. Our studies suggest not only that the two hPR isotypes are functionally quite different, but also that some of the agonist-like transcriptional effects of antagonist-occupied B-receptors proceed through novel mechanisms.

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				J. E. O'Brien, T. J. Peterson, M. H. Tong, E.-J. Lee, L. E. Pfaff, S. C. Hewitt, K. S. Korach, J. Weiss, and J. L. Jameson Estrogen-induced Proliferation of Uterine Epithelial Cells Is Independent of Estrogen Receptor {alpha} Binding to Classical Estrogen Response Elements J. Biol. Chem., September 8, 2006; 281(36): 26683 - 26692. [Abstract] [Full Text] [PDF]

				R. Shao, E. Egecioglu, B. Weijdegard, K. Ljungstrom, C. Ling, J. Fernandez-Rodriguez, and H. Billig Developmental and hormonal regulation of progesterone receptor A-form expression in female mouse lung in vivo: interaction with glucocorticoid receptors. J. Endocrinol., September 1, 2006; 190(3): 857 - 870. [Abstract] [Full Text] [PDF]

				Q. Xu, N. Ohara, W. Chen, J. Liu, H. Sasaki, A. Morikawa, R. Sitruk-Ware, E. D.B. Johansson, and T. Maruo Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells Hum. Reprod., September 1, 2006; 21(9): 2408 - 2416. [Abstract] [Full Text] [PDF]

				S. K. Mani, A. M. Reyna, J. Z. Chen, B. Mulac-Jericevic, and O. M. Conneely Differential Response of Progesterone Receptor Isoforms in Hormone-Dependent and -Independent Facilitation of Female Sexual Receptivity Mol. Endocrinol., June 1, 2006; 20(6): 1322 - 1332. [Abstract] [Full Text] [PDF]

				H. N. Jabbour, R. W. Kelly, H. M. Fraser, and H. O. D. Critchley Endocrine Regulation of Menstruation Endocr. Rev., February 1, 2006; 27(1): 17 - 46. [Abstract] [Full Text] [PDF]

				J. D. Graham, M. L. Yager, H. D. Hill, K. Byth, G. M. O'Neill, and C. L. Clarke Altered Progesterone Receptor Isoform Expression Remodels Progestin Responsiveness of Breast Cancer Cells Mol. Endocrinol., November 1, 2005; 19(11): 2713 - 2735. [Abstract] [Full Text] [PDF]

				N. Chabbert-Buffet, G. Meduri, P. Bouchard, and I. M. Spitz Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications Hum. Reprod. Update, May 1, 2005; 11(3): 293 - 307. [Abstract] [Full Text] [PDF]

				S. Mesiano Myometrial Progesterone responsiveness and the Control of Human Parturition Reproductive Sciences, May 1, 2004; 11(4): 193 - 202. [Abstract] [PDF]

				J. Wu, J. Richer, K. B. Horwitz, and S. M. Hyder Progestin-Dependent Induction of Vascular Endothelial Growth Factor in Human Breast Cancer Cells: Preferential Regulation by Progesterone Receptor B Cancer Res., March 15, 2004; 64(6): 2238 - 2244. [Abstract] [Full Text] [PDF]

ARTICLES

Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors [published erratum appears in Mol Endocrinol 1993 Nov;7(11):1378]

				R. L. Arnett-Mansfield, A. deFazio, P. A. Mote, and C. L. Clarke Subnuclear Distribution of Progesterone Receptors A and B in Normal and Malignant Endometrium J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1429 - 1442. [Abstract] [Full Text] [PDF]

				W. Sereepapong, P. Chotnopparatpattara, S. Taneepanichskul, R. Markham, P. Russell, and I. S. Fraser Endometrial progesterone and estrogen receptors and bleeding disturbances in depot medroxyprogesterone acetate users Hum. Reprod., March 1, 2004; 19(3): 547 - 552. [Abstract] [Full Text] [PDF]

				C. L. Smith and B. W. O'Malley Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators Endocr. Rev., February 1, 2004; 25(1): 45 - 71. [Abstract] [Full Text] [PDF]

				V. C. L. Lin, C. T. Woon, S. E. Aw, and C. Guo Distinct Molecular Pathways Mediate Progesterone-Induced Growth Inhibition And Focal Adhesion Endocrinology, December 1, 2003; 144(12): 5650 - 5657. [Abstract] [Full Text] [PDF]

				H. A. Molenda, C. P. Kilts, R. L. Allen, and M. J. Tetel Nuclear Receptor Coactivator Function in Reproductive Physiology and Behavior Biol Reprod, November 1, 2003; 69(5): 1449 - 1457. [Abstract] [Full Text] [PDF]

				X.-L. Zhang, D. Zhang, F. J. Michel, J. L. Blum, F. A. Simmen, and R. C. M. Simmen Selective Interactions of Kruppel-like Factor 9/Basic Transcription Element-binding Protein with Progesterone Receptor Isoforms A and B Determine Transcriptional Activity of Progesterone-responsive Genes in Endometrial Epithelial Cells J. Biol. Chem., June 6, 2003; 278(24): 21474 - 21482. [Abstract] [Full Text] [PDF]

				R. Shao, E. Markstrom, P. A. Friberg, M. Johansson, and H. Billig Expression of Progesterone Receptor (PR) A and B Isoforms in Mouse Granulosa Cells: Stage-Dependent PR-Mediated Regulation of Apoptosis and Cell Proliferation Biol Reprod, March 1, 2003; 68(3): 914 - 921. [Abstract] [Full Text] [PDF]

				S. A. Leonhardt and D. P. Edwards Mechanism of Action of Progesterone Antagonists Experimental Biology and Medicine, December 1, 2002; 227(11): 969 - 980. [Abstract] [Full Text]

				X. Fang, S. Wong, and B. F. Mitchell Messenger RNA for progesterone receptor isoforms in the late-gestation rat uterus Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1167 - E1172. [Abstract] [Full Text] [PDF]

				H. Abdel-Hafiz, G. S. Takimoto, L. Tung, and K. B. Horwitz The Inhibitory Function in Human Progesterone Receptor N Termini Binds SUMO-1 Protein to Regulate Autoinhibition and Transrepression J. Biol. Chem., September 6, 2002; 277(37): 33950 - 33956. [Abstract] [Full Text] [PDF]