Exploring the Role of Ubiquitination in Progesterone Receptor Transcriptional Activation and Turnover in Breast Cancer Cells

摘要

Progesterone Receptors (PR) play important roles in both normal breast development and in the development and progression of breast cancers. PR action contributes to cell growth and survival in the presence of progestins and/or growth factors. The growth factor inputs can create receptors with increased transcription in response to lower concentrations of progestins, or receptors hypersensitive to ligand. Post-translational modifications such as ubiquitination and SUMOylation may be mediating these effects. The goal of these studies is to elucidate the functional consequences of the post- translational modifications, specifically, phosphorylationubiquitination and SUMOylation on PR, and to determine the temporal and functional relationship between these modifications. To accomplish this goal mutants of various phosphorylation sites, conjugation sites and consensus sequences have been generated to create receptors deficient in one or more of these modifications. Our preliminary data suggests that S294A PR-B has increased sumoylation relative to wt PR-B, whereas S294A PR-B is unable to be ubiquitinated. Phosphorylation may be differentially regulating these modifications. Transcription reporter assays with S294 phosphomimic mutant PR-B display heightened transcription and the mutant deficient in sumoylation indicate SUMO is a negative regulator of PR transcriptional activity. Phosphorylation of PR by growth factor pathways differentially regulates ubiquitination and SUMOylation of the receptor mediating changes in hormone responsiveness of breast caner.