Abstract
BackgroundCovalent 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.ResultsThe 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.ConclusionWe 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.
Highlights
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 specific protease (SENP) and Progesterone receptors (PR) deSUMOylation SUMOylation and the promoter context of PR transcriptional synergy Figure 1A is a schematic of PR-B and PR-A showing location of the single ψKxE SUMO-conjugation motif centered at K388 of PR-B
PRs are major markers in breast cancer. Their presence indicates that a tumor is hormone-dependent and a candidate for endocrine therapies
Summary
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. Ubiquitination for example, promotes ligand-dependent PR protein downregulation via proteasomal degradation, which paradoxically maximizes transcriptional activity [17]. Because these modifications are reversible, enzymes that dephosphorylate, deacetylate, deubiquitinate and deSUMOylate PRs alter activity [16,18,19,20], so that permutations of these modifications undoubtedly play a large role in the complex signaling patterns ascribed to the receptors [1]
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