Both isoforms are heavily post translationally modified. PR N termini contain key regulatory phosphorylation sites as well as a SUMOylation site investigated herein. PR B, but not PR A, is phosphorylated on Ser294 in cell Oligomycin A chemical structure culture and in vivo. Upon ligand binding, both PR isoforms are rapidly SUMOylated at Lys388. SUMOylation occurs via the covalent Inhibitors,Modulators,Libraries attachment of a small ubiquitin like modifier peptide to lysine residues of substrate molecules, primarily at consensus SUMOylation motifs through an ATP dependent enzymatic mechanism, similar to that of ubiquitination. Substrate SUMOylation often alters protein protein interactions, subcellular location, protein stability, and or enzyme or tran scriptional activities. Recently, Daniel et al.

discovered that PR B phosphory lation at Ser294, in response to activated mitogen activated protein kinases or cell cycle dependent protein kinase two, prevents progestin induced rapid Inhibitors,Modulators,Libraries SUMOylation at Lys388. Additionally, Ser294 phosphorylation induced antagonism of PR SUMOylation derepressed PR transcriptional activity at selected breast cancer associated gene promoters, namely HBEGF, STC1 and IRS1, phospho PR dependent upregulation of the breast cancer associated drivers, STC1 and IRS, occurred in the absence of progestins. Pro moter structure is a key determinant of reporter gene promoter recognition by SUMOylated glucocorticoid receptors, while much less is known about how steroid receptor SUMOylation alters the regulation of endo genous genes. To date, only a few endogenous genes have been shown to be sensitive to PR SUMOylation.

We propose that PR acts Inhibitors,Modulators,Libraries as a sensor for activated mitogenic protein kinases frequently elevated in human breast cancer, under the influence of elevated Ser294 phosphorylation, genes that are sensitive to PR SUMOylation may instead cooperate to drive breast cancer cell proliferation and pro survival signaling. A phospho PR gene signature may iden tify a subset of human breast cancer patients likely to respond to endocrine therapies that contain a selective antiprogestin. We addressed Inhibitors,Modulators,Libraries mechanisms of PR promoter selectivity related to dynamic post translational events. We employed whole genome expression analysis to identify genes that are differentially regulated by wild type and SUMO deficient PR B and explored the mechanisms responsible for altered PR pro moter selectivity. Our findings implicate SUMO deficient phospho PR B in the selective regulation of genes that are important for breast cancer cell proliferation and are pro survival, and Inhibitors,Modulators,Libraries suggest that phosphorylated and deSU MOylated PRs may be important Perifosine mw drivers of the ERBB2 phenotype associated with rapid breast cancer tumor progression.