Dual roles for the phosphatase PPM1D in regulating progesterone receptor function.
Although protein phosphatase magnesium-dependent 1 delta (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.
Proia
David A
DA
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Nannenga
Bonnie W
BW
Donehower
Lawrence A
LA
Weigel
Nancy L
NL
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000737:chemistry; D010749:Phosphoprotein Phosphatases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011374:Progesterone / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D009363:Neoplasm Proteins; D011725:Pyridines; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; D013256:Steroids; D016159:Tumor Suppressor Protein p53; D011374:Progesterone; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole