This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kahmann, S. Articles by Klein-Hitpass, L. Search for Related Content PubMed PubMed Citation Articles by Kahmann, S. Articles by Klein-Hitpass, L.

Synergistic Enhancement of PR_B-Mediated RU486 and R5020 Agonist Activities through Cyclic Adenosine 3',5'-Monophosphate Represents a Delayed Primary Response

Institut für Zellbiologie (Tumorforschung) Universitätsklinikum D-45122 Essen, Germany

Activators of protein kinase A have been shown to affect the transactivation potential of progestins and antiprogestins. To analyze the mechanisms and factors involved, we have created HeLa and CV1 cell clones stably expressing isoform B of progesterone receptor. In the HeLa cell background, the progesterone antagonist RU486 significantly induces progesterone-regulatable reporter genes, and this agonistic effect is synergistically enhanced by elevating cAMP or through overexpression of protein kinase A catalytic subunit. In contrast, in CV1 cells containing functional progesterone receptors no agonist activity of RU486 could be detected, suggesting the involvement of cell specifically expressed factors. In a PR_B-positive HeLa cell clone containing stably integrated copies of a thymidine kinase-luciferase reporter gene with two progesterone response elements, we observed a complete loss of RU486 antagonist potential upon cotreatment with cAMP for 25 h while partial antagonist potential was maintained in a 5-h experiment. This result shows that, particularly in the presence of protein kinase A activators, the duration of hormone treatment is a crucial parameter in the evaluation of antagonist properties of antiprogestins. A detailed analysis of the kinetics of the hormone effects on transcription revealed that the onset of cAMP/RU486 synergism is delayed relative to the responses induced by RU486 or R5020 alone. Moreover, partial inhibition of protein synthesis by cycloheximide completely abolished cAMP/RU486 synergism while R5020 and RU486 responses were not inhibited. Together, these data indicate that cAMP/RU486 synergism is a delayed primary response requiring the intermediate induction of an essential factor.

This article has been cited by other articles:

				A. A. Goyeneche, R. W. Caron, and C. M. Telleria Mifepristone Inhibits Ovarian Cancer Cell Growth In vitro and In vivo Clin. Cancer Res., June 1, 2007; 13(11): 3370 - 3379. [Abstract] [Full Text] [PDF]

				A. Shatnawi, T. Tran, and M. Ratnam R5020 and RU486 Act as Progesterone Receptor Agonists to Enhance Sp1/Sp4-Dependent Gene Transcription by an Indirect Mechanism Mol. Endocrinol., March 1, 2007; 21(3): 635 - 650. [Abstract] [Full Text] [PDF]

				Q. Ji, L. Chang, F. Z. Stanczyk, M. Ookhtens, A. Sherrod, and A. Stolz Impaired Dihydrotestosterone Catabolism in Human Prostate Cancer: Critical Role of AKR1C2 as a Pre-Receptor Regulator of Androgen Receptor Signaling Cancer Res., February 1, 2007; 67(3): 1361 - 1369. [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]

				G. Lazennec, L. Canaple, D. Saugy, and W. Wahli Activation of Peroxisome Proliferator-Activated Receptors (PPARs) by Their Ligands and Protein Kinase A Activators Mol. Endocrinol., December 1, 2000; 14(12): 1962 - 1975. [Abstract] [Full Text]

				P. E. Chappell, J. Lee, and J. E. Levine Stimulation of Gonadotropin-Releasing Hormone Surges by Estrogen. II. Role of Cyclic Adenosine 3',5'-Monophosphate Endocrinology, April 1, 2000; 141(4): 1486 - 1492. [Abstract] [Full Text] [PDF]

				D. Szapary, Y. Huang, and S. S. Simons Jr. Opposing Effects of Corepressor and Coactivators in Determining the Dose-Response Curve of Agonists, and Residual Agonist Activity of Antagonists, for Glucocorticoid Receptor-Regulated Gene Expression Mol. Endocrinol., December 1, 1999; 13(12): 2108 - 2121. [Abstract] [Full Text]

				L. Vaßen, W. Wegrzyn, and L. Klein-Hitpass Human Insulin Receptor Substrate-2 (IRS-2) Is a Primary Progesterone Response Gene Mol. Endocrinol., March 1, 1999; 13(3): 485 - 494. [Abstract] [Full Text]