SUMOylation of the ING1b tumor suppressor regulates gene transcription

TY - JOUR

T1 - SUMOylation of the ING1b tumor suppressor regulates gene transcription

AU - Satpathy, Shankha

AU - Guérillon, Claire

AU - Kim, Tae-Sun

AU - Bigot, Nicolas

AU - Thakur, Satbir

AU - Bonni, Shirin

AU - Riabowol, Karl

AU - Pedeux, Rémy

N1 - © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

PY - 2014/10

Y1 - 2014/10

N2 - 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.

AB - 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.

KW - Amino Acid Motifs

KW - Cytokines

KW - Gene Expression Regulation

KW - Genes, Tumor Suppressor

KW - HEK293 Cells

KW - Homeodomain Proteins

KW - Humans

KW - Lysine

KW - Promoter Regions, Genetic

KW - Protein Inhibitors of Activated STAT

KW - RNA-Binding Proteins

KW - Receptors, Cytoplasmic and Nuclear

KW - Sumoylation

KW - Tumor Suppressor Proteins

KW - Ubiquitin-Conjugating Enzymes

KW - Ubiquitins

U2 - 10.1093/carcin/bgu126

DO - 10.1093/carcin/bgu126

M3 - Journal article

C2 - 24903338

SN - 0143-3334

VL - 35

SP - 2214

EP - 2223

JO - Carcinogenesis

JF - Carcinogenesis

IS - 10

ER -