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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Retracted Publication
MeSH terms
-
Amino Acid Sequence
-
Angiopoietin-2 / genetics
-
Angiopoietin-2 / metabolism*
-
Animals
-
Cell Line
-
Gene Expression Regulation / drug effects
-
Gene Expression Regulation / physiology
-
Glycolysis / physiology*
-
Humans
-
Mice
-
Models, Biological
-
Molecular Sequence Data
-
Promoter Regions, Genetic
-
Pyruvaldehyde / metabolism*
-
Pyruvaldehyde / pharmacology
-
RNA, Messenger / biosynthesis
-
Rats
-
Repressor Proteins / drug effects
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism*
-
Retina / cytology
-
Retina / drug effects
-
Retina / metabolism
-
Sin3 Histone Deacetylase and Corepressor Complex
-
Sp1 Transcription Factor / metabolism
-
Sp3 Transcription Factor / metabolism
-
Transcription, Genetic / drug effects
-
Transcription, Genetic / physiology*
-
Transcriptional Activation
-
Up-Regulation
Substances
-
Angiopoietin-2
-
RNA, Messenger
-
Repressor Proteins
-
SIN3A transcription factor
-
Sp1 Transcription Factor
-
Sp3 Transcription Factor
-
Pyruvaldehyde
-
Sin3 Histone Deacetylase and Corepressor Complex