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PNAS 99 (2): 949-954

Copyright © 2002 by the National Academy of Sciences.


Tumor necrosis factor-induced modulation of glyoxalase I activities through phosphorylation by PKA results in cell death and is accompanied by the formation of a specific methylglyoxal-derived AGE

Franky Van Herreweghe*, Jianqiang Mao{dagger}, Frank W. R. Chaplen{ddagger}, Johan Grooten{dagger}, Kris Gevaert*, Joël Vandekerckhove*, and Katia Vancompernolle*,{dagger},§

Departments of *Medical Protein Research and {dagger}Molecular Biology, Ghent University and Flanders Interuniversity Institute for Biotechnology, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium; and {ddagger}Department of Bioengineering, Oregon State University, 116 Gilmore Hall, Corvallis, OR 97331

Received for publication August 20, 2001.

Abstract: Tumor necrosis factor (TNF)-induced cell death in the fibrosarcoma cell line L929 is a caspase-independent process that is characterized by increased production of reactive oxygen species (ROS) in the mitochondria. To elucidate this ROS-dependent cell death pathway, a comparative study of the phosphoproteins present in TNF-treated and control cells was performed. Here we report that TNF induces an increased phosphorylation of glyoxalase I that is mediated by protein kinase A and required for cell death. We also show that TNF induces a substantial increase in intracellular levels of methylglyoxal (MG) that leads to the formation of a specific MG-derived advanced glycation end product and that this formation occurs as a consequence of increased ROS production. These data indicate that MG modification of proteins is a targeted process and that MG may thus function as a signal molecule during the regulation of cell death. Furthermore, we provide evidence that the TNF-induced phosphorylation of glyoxalase I is not involved in detoxification of MG by means of the glyoxalase system, but that phosphorylated glyoxalase I is on the pathway leading to the formation of a specific MG-derived advanced glycation end product.

§ To whom reprint requests should be addressed at the present address: Department of Medical Protein Research, Albert Baertsoenkaai 3, 9000 Ghent, Belgium. E-mail: katia.vancompernolle{at}

Edited by Anthony Cerami, The Kenneth S. Warren Institute, Tarrytown, NY, and approved October 31, 2001

This paper was submitted directly (Track II) to the PNAS office.

Kim, Y. H. & Kim, S. S. (2001) Cancer Detect. Prev. 24, Suppl. 1 (abstr.).

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