Dual Roles for the Phosphatase PPM1D in Regulating Progesterone Receptor Function

Abstract

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.

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

“…PPM1D activation results in negative regulation of P53 function and other tumour suppressor pathways by selective inactivation of P38 kinase (Fiscella et al, 1997;Takekawa et al, 2000;Bulavin et al, 2004). Additional functions for PPM1D include the regulation of the base excision pathway of DNA repair (Lu et al, 2004), progesterone receptor function (Proia et al, 2006), the homoeostatic regulation of the checkpoint kinases CHK1 and CHK2 (Lu et al, 2005;Fujimoto et al, 2006;Nannenga et al, 2006;OlivaTrastoy et al, 2006;Yoda et al, 2006;Yu et al, 2006) and the activation of ataxia-telangiectasia mutated (Shreeram et al, 2006), all of which may also contribute to the oncogenic effects of PPM1D overexpression. Mice deficient in Ppm1d are viable, with only minor defects in immune function and spermatogenesis (Choi et al, 2002).…”

DUSP22/LMW-DSP2 regulates estrogen receptor-α-mediated signaling through dephosphorylation of Ser-118

“…Although the phosphatase Cdc25B stimulates ERa activity, the stimulation is independent of the phosphatase activity of Cdc25B (Ma et al, 2001). Protein phosphatase magnesium-dependent 1d also stimulates ERa activity through an indirect interaction (Proia et al, 2006). We here show the first example of an estrogen-induced DSP whose activity is required for optimal regulation of ERa-mediated transcription.…”

Genetic Alterations and Oncogenic Pathways Associated with Breast Cancer Subtypes

“…It encodes a forkhead transcription factor, which is required for ER-mediated transcriptional activation of many transcriptional targets (50,51). Within the amplicon on 17q23 (associated with ER + /PR + and HER2 + cancers) there are several genes that have evidence of oncogenic activity (52)(53)(54)(55). The only gene to meet all three criteria in our prioritization is PPM1D.…”

“…The only gene to meet all three criteria in our prioritization is PPM1D. PPM1D activity has been shown to not only lead to inactivation of mitogen-activated protein kinase and p53 but also to stimulate ER and PR activity (53), again suggesting a relationship with hormone receptordependent cancers. However, the 17q23 amplification also includes other candidate protein-coding oncogenes and mir-21, a microRNA gene with oncogenic properties known to be …”