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

Abstract

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.

Rap2b, a novel p53 target, regulates p53-mediated pro-survival function

“…Previous studies by others have identified several p53 target genes, such as Glx2, Hzf, Cox-2 and IRF2BP2, that counter the apoptosis induced by p53. 11,15,46,47 The cellular consequences of the reduction of Rap2b and these other genes are reduced the levels of Rap2b in both p53 +/+ and p53 −/− HCT116 cells (Fig. 7A).…”

“…[11][12][13][14] Third, some p53 targets, for example Glx2 (also called glyoxalase II) and Cdkn1a, regulate the survival of cells after DNA damage but do not affect the expression of other p53 targets. 15 Last, the levels of p53 in response to stresses also affect the outcome of various stresses. 16 These individual events could also cooperate to regulate the life and death decisions controlled by p53.…”

Glyoxalase I in Tumor Cell Proliferation and Survival and as a Potential Target for Anticancer Therapy

“…Mitochondrial GLO2, with a molecular mass of 33.9 kDa and an isoelectric point of 8.3, is directed to the mitochondrial matrix, and cytosolic GLO2, with a molecular mass of 28.8 kDa and isoelectric point of 8.3, is mainly involved in detoxification [5,6,12]. Intron 1 of GLO2 contains a specific responsive element, which can be bound and activated by transcription factors p63 and p73, thereby up-regulating GLO2 expression [13]. GLO2 is a thiolesterase and can specifically catalyze the conversion of S-D-lactoylglutathione to non-toxic D-lactate and reforming GSH [2].…”

Two d-2-Hydroxy-acid Dehydrogenases in Arabidopsis thaliana with Catalytic Capacities to Participate in the Last Reactions of the Methylglyoxal and β-Oxidation Pathways

“…MG (CH 3 -CO-CHO; see structure in Fig. 4) is a cytotoxic compound formed primarily as a by-product of glycolysis through nonenzymatic phosphate elimination from dihydroxyacetone phosphate and glyceraldehyde 3-phosphate (15), and its production in various plants is enhanced under stress conditions such as salt, drought, cold, and heavy metal stress (16,17). Moreover, the overexpression of glyoxalase I or II was shown to confer resistance to salt stress in tobacco and rice (17,18).…”