title: SUMOylation of the ING1b tumor suppressor regulates gene transcription.
abstract: The INhibitor of Growth (ING) proteins are encoded as multiple isoforms in five ING genes (ING1 -5) and act as type II tumor suppressors. They are growth inhibitory when overexpressed and are frequently mislocalized or downregulated in several forms of cancer. ING1 and ING2 are stoichiometric members of histone deacetylase complexes, whereas ING3-5 are stoichiometric components of different histone acetyltransferase complexes. The INGs target these complexes to histone marks, thus acting as epigenetic regulators. ING proteins affect angiogenesis, apoptosis, DNA repair, metastasis and senescence, but how the proteins themselves are regulated is not yet clear. Here, we find a small ubiquitin-like modification (SUMOylation) of the ING1b protein and identify lysine 193 (K193) as the preferred ING1b SUMO acceptor site. We also show that PIAS4 is the E3 SUMO ligase responsible for ING1b SUMOylation on K193. Sequence alignment reveals that the SUMO consensus site on ING1b contains a phosphorylation-dependent SUMOylation motif (PDSM) and our data indicate that the SUMOylation on K193 is enhanced by the S199D phosphomimic mutant. Using an ING1b protein mutated at the major SUMOylation site (ING1b E195A), we further demonstrate that ING1b SUMOylation regulates the binding of ING1b to the ISG15 and DGCR8 promoters, consequently regulating ISG15 and DGCR8 transcription. These results suggest a role for ING1b SUMOylation in the regulation of gene transcription.
authors.affiliation: Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada, Present address: The Novo Nordisk Foundation Center for Protein Research, Copenhagen, Denmark.
authors.forename: Shankha
authors.initials: S
authors.lastname: Satpathy
authors.affiliation: INSERM U917, Microenvironnement et Cancer, 350043 Rennes, France, Université de Rennes 1, 350043 Rennes, France and.
authors.forename: Claire
authors.initials: C
authors.lastname: Guérillon
authors.affiliation: Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Tae-Sun
authors.initials: TS
authors.lastname: Kim
authors.affiliation: INSERM U917, Microenvironnement et Cancer, 350043 Rennes, France, Université de Rennes 1, 350043 Rennes, France and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bigot
authors.affiliation: INSERM U917, Microenvironnement et Cancer, 350043 Rennes, France.
authors.forename: Satbir
authors.initials: S
authors.lastname: Thakur
authors.affiliation: INSERM U917, Microenvironnement et Cancer, 350043 Rennes, France.
authors.forename: Shirin
authors.initials: S
authors.lastname: Bonni
authors.affiliation: Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada, karl@ucalgary.ca.
authors.forename: Karl
authors.initials: K
authors.lastname: Riabowol
authors.affiliation: INSERM U917, Microenvironnement et Cancer, 350043 Rennes, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Pedeux
mesh_terms: D020816:Amino Acid Motifs; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D058207:Sumoylation; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D016207:Cytokines; C474043:DGCR8 protein, human; D018398:Homeodomain Proteins; C444654:ING2 protein, human; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C074034:ISG15 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D008239:Lysine