Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2

摘要: Human progesterone receptors (PR) are phosphorylated by cyclin-dependent protein kinase 2 (CDK2) at multiple sites, including Ser400. Herein, we have addressed the significance of phosphorylation this residue. PR phospho-Ser400-specific antibodies revealed regulated Ser400 in response to progestins and mitogens, correlated with increased CDK2 levels activity. Expression cyclin E elevated activity downregulated independently ligand. Similarly, overexpression activated mutant transcriptional absence presence progestin. Mutation alanine (S400A) blocked CDK2-induced absence, but not presence, was unresponsive breast cancer cells p27, RNA interference knock-down p27 partially restored ligand-independent activation. p27−/− mouse embryonic fibroblasts, wild-type (wt) S400A induced nuclear localization unliganded wt PR; liganded exhibited delayed accumulation. These studies demonstrate that regulates via Ser400, thus revealing a novel mechanism for upregulated human expressing altered cell cycle regulatory molecules.