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.
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.
Van Herreweghe
Franky
F
Department of Medical Protein Research, Ghent University and Flanders Interuniversity Institute for Biotechnology, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium.
Mao
Jianqiang
J
Chaplen
Frank W R
FW
Grooten
Johan
J
Gevaert
Kris
K
Vandekerckhove
Joël
J
Vancompernolle
Katia
K
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000096:biosynthesis*; D007791:Lactoylglutathione Lyase / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011765:Pyruvaldehyde / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D011765:Pyruvaldehyde; D017868:Cyclic AMP-Dependent Protein Kinases; D007791:Lactoylglutathione Lyase