期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 34, 页码 14287-14292出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0905118106
关键词
HDAC; phosphorylation; sumoylation
资金
- National Institutes of Health [R01 CA123763, R21 CA116790]
In advanced breast tumors, protein kinases are upregulated and steroid hormone receptors often function independently of ligand. Herein, we explored mechanisms of ligand-independent progesterone receptor (PR) activity. We showed previously that growth factor-induced phosphorylation of PR Ser-294 blocks PR Lys-388 sumoylation. SUMO-deficient mutant PR-B (K388R) thus provides a model receptor for the study of PR function in the context of high kinase activities. T47D cells stably expressing K388R PR-B exhibited increased ligand-independent proliferation and growth in soft agar relative to cells expressing wt PR-B or phospho-mutant (sumoylated) S294A PR-B. Expression of selected PR target genes (HB-EGF, IRS-1, and STC1) was significantly elevated in cells containing desumoylated (K388R) PR-B. Basal PR transcriptional activity occurred independently of progestins, was increased by activated CDK2, and attenuated by RU486. Notably, ChIP assays demonstrated that K388R PR-B and SRC1 were constitutively recruited to the STC1 promoter in the absence of progestin; PR Lys-388 sumoylation was required for HDAC3 recruitment. Knock-down of STC1 inhibited proliferation of cells expressing K388R PR-B. These data suggest a mechanism whereby phosphorylated, and thus desumoylated, PRs mediate increased expression of growth promoting genes. Our data explain why breast cancer models often remain insensitive to progestins, but are growth-inhibited by antiprogestins, and underscore the need to target PR-B and associated kinase activities as part of breast cancer therapy.
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