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J. Biol. Chem., Vol. 281, Issue 36, 26702-26713, September 8, 2006

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Glyoxalase II, a Detoxifying Enzyme of Glycolysis Byproduct Methylglyoxal and a Target of p63 and p73, Is a Pro-survival Factor of the p53 Family^*

From the Department of Cell Biology, University of Alabama, Birmingham, Alabama 35294-0005

The p53 family proteins are transcription factors and have both common and distinct functions. p53 is a classic tumor suppressor, whereas p63 and p73 have fundamental functions in development. To gain an insight into the functional diversities among the p53 family, target genes specifically regulated by p63 and p73 were examined. Here, we found that the GLX2 gene, which encodes glyoxalase II enzyme, is up-regulated by p63 and p73. Accordingly, a specific responsive element was found in intron 1 of the GLX2 gene, which can be activated and bound by p63 and p73. We also found that, upon overexpression, the cytosolic, but not the mitochondrial, GLX2 inhibits the apoptotic response of a cell to methylglyoxal, a by-product of glycolysis. Likewise, we showed that cells deficient in GLX2 are hypersensitive to methylglyoxal-induced apoptosis. Interestingly, a deficiency in GLX2 also enhances the susceptibility of a cell to DNA damage-induced apoptosis in a p53-dependent manner. These observations reveal a novel link between the p53 family and the glyoxalase system. Given that methylglyoxal is frequently generated under both physiological and pathological conditions, we postulate that GLX2 serves as a pro-survival factor of the p53 family and plays a critical role in the normal development and in the pathogenesis of various human diseases, including cancer, diabetes, and neurodegenerative diseases.

Received for publication, May 17, 2006 , and in revised form, July 7, 2006.

^* This work was supported by National Institutes of Health Grants CA102188, CA081237, and CA076069. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell Biology, University of Alabama, MCLM 660, 1530 3rd Ave. S., Birmingham, AL 35294-0005. Tel.: 205-975-1798; Fax: 205-934-0950; E-mail: xchen{at}uab.edu.

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