Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1.
SUMO-1 (small ubiquitin-like modifier) conjugation regulates the subcellular localization, stability, and activity of a variety of proteins. We show here that SUMO-1 overexpression markedly enhances progesterone receptor (PR)-mediated gene transcription. PR undergoes a sumoylation at lysine 388 located in its N-terminal domain. However, sumoylation of the receptor is not responsible for enhanced transcription because substitution of its target lysine did not abolish the effect of SUMO-1 and even converted the receptor into a slightly more active transactivator. Furthermore estrogen receptor alpha (ERalpha)-driven transcription is also enhanced by SUMO-1 overexpression contrasting with the absence of sumoylation of this receptor. We thus analyzed SUMO-1 conjugation to the steroid receptor coactivator SRC-1. We showed that this protein contains two major sites of conjugation at Lys-732 and Lys-774. Sumoylation was shown to increase PR-SRC-1 interaction and to prolong SRC-1 retention in the nucleus. It did not prevent SRC-1 ubiquitinylation and did not exert a clear effect on the stability of the protein. Overexpression of SUMO-1 enhanced PR-mediated gene transcription even in the presence of non-sumoylated mutants of SRC-1. This observation suggests that among the many protein partners involved in steroid hormone-mediated gene regulation several are probably targets of SUMO-1 modification.
Chauchereau
Anne
A
INSERM U135, Hormones, Gènes, and Reproduction, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France.
Amazit
Larbi
L
Quesne
Monique
M
Guiochon-Mantel
Anne
A
Milgrom
Edwin
E
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D016384:Consensus Sequence; D003593:Cytoplasm / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D016296:Mutagenesis; D056920:Nuclear Receptor Coactivator 1; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology
D011980:Receptors, Progesterone; D025842:SUMO-1 Protein; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1