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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 275-286 |
| Number of pages | 12 |
| Journal | Cell |
| Volume | 124 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 27 2006 |
Funding
These studies were supported by grants from the National Institutes of Health (DK 33861 and AG 021654) to M.B. and to the Albert Einstein College of Medicine Diabetes Research and Training Center (DK 20541) and by grants from the Juvenile Diabetes Research Foundation (4-2004-804) to M.B. We are grateful for the generosity of Drs. G.D. Yancopoulos and P.C. Maisonpierre for the pGL3-mANG-2(short)-Luc reporter plasmid, Dr. R.M. Evans for mouse Gal4mSin3A, Dr. G.W. Hart for rat OGT cDNA, OGT antibody, and human His-tagged GlcNAcase cDNA. We thank Dr. L. Rossetti for his critical reading of this manuscript.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
