Control of progesterone receptor transcriptional synergy by SUMOylation and deSUMOylation

The present studies address mechanisms underlying this transcriptional synergy by using SUMOylation deficient PR mutants and PR specifically deSUMOylated by Sentrin-specific proteases (SENPs). We show that deSUMOylation of a small pool of receptors by catalytically competent SENPs globally modulates the cooperativity-driven transcriptional synergy between PR observed on exogenous promoters containing at least two progesterone-response elements (PRE2). This occurs in part by raising PR sensitivity to ligands. The C-terminal ligand binding domain of PR is required for the transcriptional stimulatory effects of N-terminal deSUMOylation, but neither a functional PR dimerization interface, nor a DNA binding domain exhibiting PR specificity, are required.We conclude that direct and reversible SUMOylation of a minor PR protein subpopulation tightly controls the overall transcriptional activity of the receptors at complex synthetic promoters. Transcriptional synergism controlled by SENP-dependent PR deSUMOylation is dissociable from MAPK-catalyzed receptor phosphorylation, from SRC-1 coactivation and from recruitment of histone deacetylases to promoters. This will provide more information for targeting PR as a part of hormonal therapy of breast cancer. Taken together, these data demonstrate that the SUMOylation/deSUMOylation pathway is an interesting target for therapeutic treatment of breast cancer.Progesterone plays a key role in the development, differentiation and maintenance of normal and malignant female tissues. Its effects are mediated by progesterone receptors (PRs), members of the steroid hormone receptor superfamily of ligand-dependent transcription factors. PRs exist as two major, functionally different [1] isoforms--PR-A (~94 kDa) and PR-B (~110 kDa). They are multidomain proteins consisting of a central DNA-binding domain (DBD); large N-termini with a proximal activation function (AF-1) common to both isoforms; a distal AF-3 in the B-upstream segment (BUS) res