title: Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription.
abstract: Methylglyoxal is a highly reactive dicarbonyl degradation product formed from triose phosphates during glycolysis. Methylglyoxal forms stable adducts primarily with arginine residues of intracellular proteins. The biologic role of this covalent modification in regulating cell function is not known. Here, we report that in retinal Müller cells, increased glycolytic flux causes increased methylglyoxal modification of the corepressor mSin3A. Methylglyoxal modification of mSin3A results in increased recruitment of O-GlcNAc transferase to an mSin3A-Sp3 complex, with consequent increased modification of Sp3 by O-linked N-acetylglucosamine. This modification of Sp3 causes decreased binding of the repressor complex to a glucose-responsive GC box in the angiopoietin-2 promoter, resulting in increased Ang-2 expression. A similar mechanism involving methylglyoxal-modification of other coregulator proteins may play a role in the pathobiology of a variety of conditions associated with changes in methylglyoxal concentration, including cancer and diabetic vascular disease.
authors.affiliation: JDRF International Center for Diabetic Complications Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Dachun
authors.initials: D
authors.lastname: Yao
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Taguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsumura
authors.forename: Richard
authors.initials: R
authors.lastname: Pestell
authors.forename: Diane
authors.initials: D
authors.lastname: Edelstein
authors.forename: Ida
authors.initials: I
authors.lastname: Giardino
authors.forename: Guntram
authors.initials: G
authors.lastname: Suske
authors.forename: Naila
authors.initials: N
authors.lastname: Ahmed
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Sarthy
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
mesh_terms: D000595:Amino Acid Sequence; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011765:Pyruvaldehyde / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D042702:Angiopoietin-2; D012333:RNA, Messenger; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D011765:Pyruvaldehyde; D056264:Sin3 Histone Deacetylase and Corepressor Complex