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Tumor Necrosis Factor-Induced Modulation of Glyoxalase I Activities

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Tumor Necrosis Factor-Induced Modulation of Glyoxalase I Activities 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†, Frank W. R. Chaplen‡, Johan Grooten†, Kris Gevaert*, Joe¨ l Vandekerckhove*, and Katia Vancompernolle*†§ Departments of *Medical Protein Research and †Molecular Biology, Ghent University and Flanders Interuniversity Institute for Biotechnology, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium; and ‡Department of Bioengineering, Oregon State University, 116 Gilmore Hall, Corvallis, OR 97331 Edited by Anthony Cerami, The Kenneth S. Warren Institute, Tarrytown, NY, and approved October 31, 2001 (received for review August 20, 2001) Tumor necrosis factor (TNF)-induced cell death in the fibrosarcoma and is ubiquitous in nature, its full biological function has never cell line L929 is a caspase-independent process that is characterized been elucidated. The work of Szent-Gyo¨rgyi suggested that by increased production of reactive oxygen species (ROS) in the GLO1 and methylglyoxal (MG) were involved in the regulation mitochondria. To elucidate this ROS-dependent cell death path- of cellular growth, but a direct mechanistic link has yet to be way, a comparative study of the phosphoproteins present in identified (reviewed in ref. 10). A major function of the glyox- TNF-treated and control cells was performed. Here we report that alase pathway is believed to be detoxification of ␣-ketoalde- TNF induces an increased phosphorylation of glyoxalase I that is hydes, especially MG. MG is a cytotoxic metabolite produced mediated by protein kinase A and required for cell death. We also primarily as a by-product of glycolysis through nonenzymatic show that TNF induces a substantial increase in intracellular levels phosphate elimination from the glycolytic pathway intermedi- of methylglyoxal (MG) that leads to the formation of a specific ates dihydroxyacetone phosphate and glyceraldehyde 3-phos- MG-derived advanced glycation end product and that this forma- phate (for a review on MG, see ref. 11). The glyoxalase system tion occurs as a consequence of increased ROS production. These requires reduced glutathione (GSH) as a cofactor and catalyzes data indicate that MG modification of proteins is a targeted process the conversion of MG to D-lactate. The substrate for GLO1 is the and that MG may thus function as a signal molecule during the hemithioacetal formed through the nonenzymatic conjugation regulation of cell death. Furthermore, we provide evidence that of MG with GSH. The product of the GLO1-catalyzed reaction the TNF-induced phosphorylation of glyoxalase I is not involved in is S-D-lactoylglutathione, which is then hydrolyzed by glyoxalase detoxification of MG by means of the glyoxalase system, but that II to D-lactate; GSH is regenerated by the action of GLO2. phosphorylated glyoxalase I is on the pathway leading to the D-Lactate is further metabolized to pyruvate in some mamma- formation of a specific MG-derived advanced glycation end lian tissues. MEDICAL SCIENCES product. Increased expression of GLO1 occurs in diabetic patients and in some tumors, such as colon carcinoma (12), breast cancer (13), umor necrosis factor (TNF) is a pleiotropic cytokine that and prostate cancer (14). Recently, it has been shown that GLO1 Tplays a role in the host defense against microorganisms and is involved in resistance of human leukemia cells to antitumor bacterial pathogens and in the pathophysiology of various dis- agent-induced apoptosis (15). Under normal physiological con- eases (1, 2). Furthermore, TNF has potent antitumor and ditions, most MG is bound to cellular proteins as adducts formed antimalignant cell effects. Depending on the cell type, cell death with Lys, Arg, and Cys residues (16, 17). Although the reaction by TNF can occur by apoptosis or necrosis (3, 4). TNF-induced with Cys is considered reversible, elevated concentrations of MG cell death in the murine fibrosarcoma cell line L929, the cell line can lead to irreversible modifications of Lys and Arg residues used in this study, is characterized by a necrosis phenotype that through formation of advanced glycation end products (AGEs) is caspase-independent and does not involve DNA fragmenta- (18). AGE formation is thought to contribute to several patho- ͞ tion, but instead requires the increased production of reactive physiological conditions, such as tissue damage after ischemia oxygen species (ROS) in the mitochondria (5–7). Much effort reperfusion (19), to aging (20), and to the development of has been directed at elucidating the molecular mechanisms of complications in diabetic patients such as blindness, neuropathy, caspase-dependent cell death, but relatively little is yet known and diabetic vascular diseases (21). about the TNF-induced ROS-dependent cell death pathway. Materials and Methods To identify signaling molecules downstream of the receptor- proximal events that are involved in this cell death pathway, Cell Lines. L929 cells were cultured in Dulbecco’s modified protein phosphorylation changes in L929 cells were examined by Eagle’s medium supplemented with heat-inactivated FCS (5% comparative two-dimensional (2D) gel electrophoresis after stimulation with TNF for 1.5 h (that is, just before cells start to This paper was submitted directly (Track II) to the PNAS office. die). Previous work has shown that TNF-induced increase in Abbreviations: AGE, advanced glycation end product; BBGD, S-p-bromobenzylglutathione oncoprotein 18 (Op18, stathmin) phosphorylation is responsible cyclopentyl diester; BHA, butylated hydroxyanisole; CHX, cycloheximide; ECL, enhanced for TNF-induced microtubule stabilization, which in turn pro- chemiluminescence; GLO1, glyoxalase I; GSH, glutathione; MG, methylglyoxal; PI, pro- motes cell death (8). Now, we demonstrate that phosphorylation pidium iodide; PKA, protein kinase A; ROS, reactive oxygen species; TNF, tumor necrosis of glyoxalase I (lactoylglutathione lyase, EC 4.4.1.5) is a key step factor; 2D, two-dimensional. in TNF-induced cell death. §To whom reprint requests should be addressed at the present address: Department of Medical Protein Research, Albert Baertsoenkaai 3, 9000 Ghent, Belgium. E-mail: The glyoxalase system, consisting of the enzymes glyoxalase I [email protected]. (GLO1) and glyoxalase II (GLO2), is an integral component of The publication costs of this article were defrayed in part by page charge payment. This cellular metabolism in mammalian systems (see review in ref. 9). article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Although the glyoxalase pathway was reported as early as 1913 §1734 solely to indicate this fact. www.pnas.org͞cgi͞doi͞10.1073͞pnas.012432399 PNAS ͉ January 22, 2002 ͉ vol. 99 ͉ no. 2 ͉ 949–954 Downloaded by guest on September 28, 2021 vol͞vol), heat-inactivated newborn calf serum (5% vol͞vol), search in a nonredundant protein database led to the identifi- ͞ ͞ penicillin (100 units ml), streptomycin (0.1 mg ml), and L- cation of the peptide NH2-FSLYFLAYEDK-COOH also be- glutamine (2 mM), at 37°C in a humidified incubator under a 5% longing to human GLO1. Again, the same peptide sequence was CO2 atmosphere. found in different mouse EST clones by using the postsource decay data and a SEQUEST search in an EST database. On the Reagents. Murine TNF was obtained from Roche Diagnostics. basis of the amino acid sequence of human GLO1, masses of Propidium iodide (PI), cycloheximide (CHX), and butylated peptide ions observed in the different RP-HPLC fractions could hydroxyanisole (BHA) (all from Sigma) were used at concen- be assigned to the identified protein. In this way, a total of 38% trations of 30 ␮M, 50 ␮g͞ml, and 100 ␮M, respectively. The PKA of the amino acid sequence of the protein was covered, again inhibitor H89 was obtained from Calbiochem. The glyoxalase I confirming the identification of GLO1. inhibitor S-p-bromobenzylglutathione cyclopentyl diester (BBGD) and the anti-glyoxalase I antibody were a kind gift from Assay of GLO1 Activity. GLO1 activity was determined by using the Dr. P. Thornalley (Department of Biological Sciences, Univer- spectrophotometric method, which monitors the initial rate of sity of Essex, United Kingdom). The monoclonal anti-MG- change in absorbance at 240 nm caused by the formation of derived AGE antibody (mAb6B) was donated by Dr. K. Uchida S-D-lactoylglutathione (26). The standard assay mixture con- (Nagoya University Graduate School of Bioagricultural Sci- tained 2-mM MG and 2-mM GSH in a sodium phosphate buffer ences, Nagoya, Japan). (50 mM, pH 6.6, 20°C). The reaction mixture was allowed to stand for 10 min before the addition of the cytosolic protein Radiolabeling of Cells and Preparation of the Subcellular Protein fraction (15–30 ␮g) to ensure the equilibration of hemithioacetal Fractions and 2D Gel Electrophoresis. These procedures were per- formation. formed as described (8). D-Lactate Measurements. D-Lactate measurements were per- Western Blotting. Proteins were separated by SDS͞12.5% PAGE formed by using the fluorometric endpoint assay with D-lactate and transferred to a poly(vinylidene difluoride) membrane dehydrogenase (27). (Hybond-P, Amersham Pharmacia). The blots were incubated with a polyclonal anti-human glyoxalase I antibody, followed by Methylglyoxal Assay. Intracellular MG was measured by using a enhanced chemiluminescence (ECL)-based detection (Amer- modification of the HPLC-based
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