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J. Biol. Chem., Vol. 280, Issue 14, 13329-13340, April 8, 2005

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Identification and Characterization of the Protein-associated Splicing Factor as a Negative Co-regulator of the Progesterone Receptor^*

Xuesen Dong, Oksana Shylnova, John R. G. Challis, and Stephen J. Lye¶

From the Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada and the Departments of Obstetrics and Gynecology and Physiology, University of Toronto, Ontario M5S 1A8, Canada

Progesterone is essential in all species for the maintenance of pregnancy, and its withdrawal is required to activate the myometrium and to initiate labor. However, unlike most other species, progesterone levels do not fall at term in humans, raising the paradox as to how labor can occur under the continued influence of progesterone. We hypothesized that an endogenous (myometrial) repressor of the progesterone receptor (PR) could induce a functional withdrawal of progesterone and hence lead to the initiation of labor. We used the human PR as bait in a protein pull-down assay and identified polypyrimidine tract-binding protein-associated splicing factor (PSF) as a PR-interacting protein. PSF functions as a potent inhibitor of PR (but not estrogen receptor) transcriptional activity in mammalian cells. It acts through two novel mechanisms, inducing degradation of the PR through the proteasomal pathway and also interfering with binding of PR to its DNA response element. Importantly, in vivo studies in rats demonstrated a dramatic increase in myometrial PSF expression at term that was temporally associated with reduced levels of the myometrial PR. Accordingly, we propose that PSF acts as a PR corepressor and contributes to the functional withdrawal of progesterone and the initiation of human labor.

Received for publication, August 11, 2004 , and in revised form, January 18, 2005.

^* This work was supported by Operating Grant MOP-42378 from the Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Center for Women's and Infants' Health, Samuel Lunenfeld Research Inst., Mount Sinai Hospital, 600 University Ave., Suite 982, Toronto, Ontario M5G 1X5, Canada. Tel.: 416-586-8640; Fax: 416-586-8857; E-mail: lye{at}mshri.on.ca.

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