title: Control of progesterone receptor transcriptional synergy by SUMOylation and deSUMOylation.
abstract: BACKGROUND
  Covalent modification of nuclear receptors by the Small Ubiquitin-like Modifier (SUMO) is dynamically regulated by competing conjugation/deconjugation steps that modulate their overall transcriptional activity. SUMO conjugation of progesterone receptors (PRs) at the N-terminal lysine (K) 388 residue of PR-B is hormone-dependent and suppresses PR-dependent transcription. Mutation of the SUMOylation motif promotes transcriptional synergy.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Endocrinology, Department of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA. hany.abdel-hafiz@ucdenver.edu
authors.forename: Hany A
authors.initials: HA
authors.lastname: Abdel-Hafiz
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Horwitz
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation; D014158:Transcription, Genetic
chemical_list: D011980:Receptors, Progesterone; D025842:SUMO-1 Protein; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1; D020929:Mitogen-Activated Protein Kinase Kinases; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human