Mechanisms underlying the control of progesterone receptor transcriptional activity by SUMOylation.
Posttranslational modification by small ubiquitin-like modifier (SUMO) is a major regulator of transcription. We previously showed that progesterone receptors (PR) have a single consensus psiKXE SUMO-conjugation motif centered at Lys-388 in the N-terminal domain of PR-B and a homologous site of PR-A. SUMOylation of the PR is hormone-dependent and has a suppressive effect on transcription of an exogenous promoter. Here we show that repression of PR activity by SUMOylation at Lys-388 is uncoupled from phosphorylation, involves synergy between tandem progesterone response elements, and is associated with lowered ligand sensitivity and slowed ligand-dependent down-regulation. However, paradoxically, cellular overexpression of SUMO-1 increases PR transcriptional activity even if Lys-388 is mutated, suggesting that the receptors are activated indirectly by other SUMOylated proteins. One of these is the coactivator SRC-1, whose binding to PR and enhancement of agonist-dependent N-/C-terminal interactions is augmented by the presence of SUMO-1. Increased transcription due to SRC-1 is independent of PR SUMOylation based on assays with the Lys-388 mutants and the pure antiprogestin ZK98299, which blocks N-/C-terminal interactions. In summary, SUMOylation tightly regulates the transcriptional activity of PR by repressing the receptors directly while activating them indirectly through augmented SRC-1 coactivation.
Abdel-Hafiz
Hany
H
Department of Medicine, Division of Endocrinology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA. hany.abdel-hafiz@ucdenver.edu
Dudevoir
Michelle L
ML
Horwitz
Kathryn B
KB
D000595:Amino Acid Sequence; D002460:Cell Line; D015536:Down-Regulation; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D056920:Nuclear Receptor Coactivator 1; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011980:Receptors, Progesterone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
D008024:Ligands; D011980:Receptors, Progesterone; D025842:SUMO-1 Protein; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1