title: Small ubiquitin-like Modifier (SUMO) modification inhibits GLI2 protein transcriptional activity in vitro and in vivo.
abstract: The Gli transcription factors are key downstream mediators of the Hedgehog (Hh) signaling pathway. How the activities of Gli transcription factors are regulated by upstream Hh signaling events and protein modifications are not fully understood. Here we show that GLI2 is conjugated by small ubiquitin-like modifier (SUMO) at lysine residues 630 and 716 in the cell. The level of GLI2 sumoylation is reduced by either mutations in six serine residues that are normally phosphorylated by protein kinase A (PKA) or stimulation by HH. This suggests that PKA phosphorylation enhances GLI2 sumoylation, whereas HH signaling inhibits it. In addition, mutation of these two lysines into arginine residues significantly increases GLI2 transcriptional activity in a cell-based reporter assay. The same mutations in the GLI2 locus also result in an increase in GLI2 activity in the mouse. Interestingly, GLI2 can interact with HDAC5 (histone deacetylase 5), but the GLI2 mutant cannot. Taken together, our results suggest that SUMO modification inhibits GLI2 transcriptional activity by recruiting HDAC5.
authors.affiliation: Department of Neurosurgery, Provincial Hospital affiliated to Shandong University, Shandong University, Jinan City, Shandong 250012, China.
authors.forename: Lizhang
authors.initials: L
authors.lastname: Han
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.forename: Baolin
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci / Q000502:physiology; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D025842:SUMO-1 Protein; D000075746:Zinc Finger Protein Gli2; D017868:Cyclic AMP-Dependent Protein Kinases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases