This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted 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 Yin, P. Articles by Bulun, S. E. Search for Related Content PubMed PubMed Citation Articles by Yin, P. Articles by Bulun, S. E. Related Collections Female Endocrinology

Progesterone Receptor Regulates Bcl-2 Gene Expression through Direct Binding to Its Promoter Region in Uterine Leiomyoma Cells

Division of Reproductive Biology Research (P.Y., Z.L., Y.-H.C., E.E.M., H.U., H.I., Q.X., S.R., J.I., J.J.K., E.X., S.E.B.), Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60611; and Department of Obstetrics, Gynecology, and Reproductive Sciences (S.T.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, 303 East Superior Street, Suite 4-123, Chicago, Illinois 60611. E-mail: s-bulun{at}northwestern.edu.

Context: Uterine leiomyomas are smooth muscle cell tumors that cause irregular uterine bleeding and pregnancy loss in many reproductive-age women. Progesterone stimulates their growth, whereas treatment with progesterone receptor (PR) antagonists or selective progesterone receptor modulators shrinks these tumors. Molecular mechanisms underlying these observations are unknown.

Objective: Bcl-2 is a key protein that inhibits apoptosis. It was proposed that growth enhancement of leiomyoma cells by progesterone was mediated via bcl-2 induction. Here we test the hypothesis that PR regulates the bcl-2 gene by directly binding to its promoter.

Results: The pure progesterone agonist R5020 increased the total number of viable primary human leiomyoma smooth muscle (LSM) cells in culture. Progesterone or R5020 (10^–6 M) significantly increased bcl-2 mRNA levels after 2 and 4 h by 9.2- and 3.4-fold, respectively, in LSM cells. Transient transfection with deletion mutants of bcl-2 promoter showed that the –1281/–258-bp region conferred responsiveness to progesterone induction in the presence of PR-A. We identified a palindromic progesterone response element (PRE) at –553/–539 bp. EMSA showed that PR in nuclear extracts from LSM cells bound specifically to this PRE. Chromatin immunoprecipitation-PCR confirmed in situ recruitment of PR to the –629/–388-bp region bearing the PRE. In vivo, bcl-2 mRNA levels correlated significantly with total PR mRNA levels in leiomyoma tissues.

Conclusion: Taken together, progesterone via PR interacts with the bcl-2 promoter to induce its expression in leiomyoma tissue. This may explain, in part, the progesterone-dependent enhancement of growth in uterine leiomyoma.

This article has been cited by other articles:

				X. Luo, P. Yin, S. Reierstad, H. Ishikawa, Z. Lin, M. E. Pavone, H. Zhao, E. E. Marsh, and S. E. Bulun Progesterone and Mifepristone Regulate L-Type Amino Acid Transporter 2 and 4F2 Heavy Chain Expression in Uterine Leiomyoma Cells J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4533 - 4539. [Abstract] [Full Text] [PDF]

				A. V. Hoekstra, E. C. Sefton, E. Berry, Z. Lu, J. Hardt, E. Marsh, P. Yin, J. Clardy, D. Chakravarti, S. Bulun, et al. Progestins Activate the AKT Pathway in Leiomyoma Cells and Promote Survival J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1768 - 1774. [Abstract] [Full Text] [PDF]

				B. Gellersen, M.S. Fernandes, and J.J. Brosens Non-genomic progesterone actions in female reproduction Hum. Reprod. Update, January 1, 2009; 15(1): 119 - 138. [Abstract] [Full Text] [PDF]