Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription

Dachun Yao, Tetsuya Taguchi, Takeshi Matsumura, Richard Pestell, Diane Edelstein, Ida Giardino, Guntram Suske, Naila Ahmed, Paul J. Thornalley, Vijay P. Sarthy, Hans Peter Hammes, Michael Brownlee

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69 Scopus citations

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 languageEnglish (US)
Pages (from-to)275-286
Number of pages12
JournalCell
Volume124
Issue number2
DOIs
StatePublished - Jan 27 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Yao, D., Taguchi, T., Matsumura, T., Pestell, R., Edelstein, D., Giardino, I., Suske, G., Ahmed, N., Thornalley, P. J., Sarthy, V. P., Hammes, H. P., & Brownlee, M. (2006). Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription. Cell, 124(2), 275-286. https://doi.org/10.1016/j.cell.2005.11.024