Phosphorylation-dependent antagonism of sumoylation derepresses progesterone receptor action in breast cancer cells.

摘要: Progesterone receptors (PRs) mediate proliferation during breast development and contribute to cancer progression, in part by synergizing with peptide growth factors. We have previously identified PR Ser294 as a key site for direct regulation of location, activity, turnover response phosphorylation events. Herein, we sought better understand how hormonal cross talk alters function. demonstrate that progestins (R5020 RU486) induce rapid (15 min) sumoylation Lys388; represses transcriptional activity on selected progesterone element-driven endogenous promoters retards ligand-induced down-regulation. Consistent this finding, show stabilized but weakly active phospho-mutant S294A PRs are heavily sumoylated. Conversely, desumoylated PR, created mutation Lys388 (K388R) or overexpression sentrin (SUMO)-specific protease desumoylating enzymes, hypersensitive low progestin concentrations. Combination K388R mutations (KRSA double-mutant PR) rescues both transcription impaired (S294A) receptors. Notably, events antagonize PR-B not PR-A sumoylation. Treatment cells epidermal factor transient expression activated mitogen-activated protein/ERK kinase cyclin-dependent protein 2 induces blocks sumoylation, thereby derepressing receptor activity; is resistant these Modulation reversible diverse signals provides mechanism isoform-specific changes hormone responsiveness. In the context elevated activities, such mammary gland phosphorylated may be undersumoylated, transcriptionally hyperactive, unstable/undetectable.