Transcriptional activity of peroxisome proliferator-activated receptor gamma is modulated by SUMO-1 modification.
Covalent modification of many transcription factors with SUMO-1 is emerging as a key role of trans-activational regulation. Here, we demonstrate that peroxisome proliferator-activated receptor (PPAR) gamma, which is a ligand-activated nuclear receptor, is modified by SUMO-1. Sumoylation of PPARgamma mainly occurs at a lysine residue within the activation function 1 domain. Furthermore, we show that the PIAS family proteins, PIAS1 and PIASxbeta, function as E3 ligases (ubiquitin-protein isopeptide ligase) for PPARgamma. PPARgamma interacts directly with PIASxbeta in a ligand-independent manner. Analysis using a PPARgamma mutant with a disrupted sumoylation site shows that modification of PPARgamma by SUMO-1 represses its transcriptional activity. Interestingly, PIASxbeta and Ubc9 enhance the transcriptional activity of PPARgamma independent of PPARgamma sumoylation. Furthermore, PPARgamma ligand-induced apoptosis in a human hepatoblastoma cell line, HepG2, is significantly enhanced by ectopic production of the sumoylation-mutant PPARgamma. These results suggest that the PPARgamma-dependent transactivation pathway seems to be modulated by SUMO-1 modification and may serve as a novel target for apoptosis-induction therapy in cancer cells.
Ohshima
Takayuki
T
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. tohshima@virus.kyoto-u.ac.jp
Koga
Hiroshi
H
Shimotohno
Kunitada
K
D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D050828:Protein Inhibitors of Activated STAT; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D002352:Carrier Proteins; D008024:Ligands; C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C476735:Pias2 protein, mouse; D000098843:Ubiquitin-Conjugating Enzyme UBC9