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J. Biol. Chem., Vol. 281, Issue 11, 7089-7101, March 17, 2006

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Dual Roles for the Phosphatase PPM1D in Regulating Progesterone Receptor Function^*

David A. Proia¹, Bonnie W. Nannenga, Lawrence A. Donehower, and Nancy L. Weigel²

From the Departments of Molecular and Cellular Biology and Microbiology and Virology, Baylor College of Medicine, Houston, Texas 77030

Although protein phosphatase magnesium-dependent 1 (PPM1D) was initially characterized as a p53-regulated phosphatase responsible for inactivation of p38 MAPK and consequent inactivation of p53, its overexpression and amplification in human breast cancers led us to assess its role in steroid hormone action. We found that PPM1D stimulated the activity of several nuclear receptors including the progesterone receptor (PR) and estrogen receptor. Although p38 MAPK inhibited PR activity, PPM1D stimulation of PR activity was greater than that achieved by a chemical inhibitor of p38 MAPK, SB202190. This suggests an additional novel function for PPM1D. Consistent with this, the transcriptional activity of endogenous PR in MCF-7 breast cancer cells was preferentially inhibited by small interfering RNA for PPM1D; SB202190 failed to reverse the inhibition. Although PPM1D phosphatase activity was required for stimulation of transcriptional activity, the activity of a PR phosphorylation site null mutant was enhanced by PPM1D, indicating that PR is not the direct target. Additional studies revealed that PPM1D enhanced the intrinsic activity of p160 coactivators such as steroid receptor coactivator-1 and promoted the interaction between PR and steroid receptor coactivator-1 in a mammalian two-hybrid assay. Neither activity was induced by SB202190. Although PPM1D stimulated PR activity in part through inhibition of p38 MAPK, its primary action is novel and independent of p38 MAPK. Thus, we speculate that PPM1D promotes breast tumor growth both by inhibiting p53 activity and by enhancing steroid hormone receptor action.

Received for publication, November 2, 2005 , and in revised form, December 12, 2005.

^* This work was supported by Public Health Service Grants R01 CA57539 (to N. L. W.), R01 CA100420 (to L. A. D.), and T32 HD07165 (to D. A. P.) and a predoctoral fellowship from the National Science Foundation (to D. A. P.). 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.

¹ Present address: Dept. of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, MA 02111.

² To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-6234; E-mail: nweigel{at}bcm.tmc.edu.

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