p73 keeps metabolic control in balance.

Both cancer cells and aging cells exhibit altered metabolic activity, which is, at least in part, due to deregulation of the p53 family members. Although several mechanisms through which p53 affects metabolisms are known, less information is available of its family member p73. In the December 15, 2013 issue of Cell Cycle, Velletri et al. report the ability of TAp73 to bind the promoter and regulate the expression of glutaminase type 2 (GLS2). In particular, the authors investigate the regulation of the TAp73/GLS2 axis during the in vitro differentiation of neuroblastoma cells and cortical neurons, including during mouse cerebellar development.

The biological response to DNA damage requires the activation of the cell death pathway by p53 or its family members. p53 is a powerful transcription factor that drives a large number of promoters, depending on its specific activators; these include novel pathways, such as the connection between IL-7Ra and telomer erosion or the silencing of repeats and noncoding RNA, as well as cell metabolism via the pathways of mevalonate or serine. Growing evidences indicate that, under specific circumstances, p53 can also come to the aid of stressed cells, functioning to protect them from damage and contributing to a survival response; the role of p53 in controlling metabolism seems to fall in this category. The p53 family member p73 is also able to regulate metabolism. In particular, recent work has shown that p73 physically binds to specific promoters and consequently controls the transcription of Cox4i1 or G6PD. The work by Velletri et al. adds GLS2 as a novel mechanism for TAp73 to regulate the normal metabolism of the cell.

Velletri et al. show that TAp73 is able to directly bind the promoter of the GLS2 gene, hence regulating its expression. In addition, in vitro experiments demonstrate that TAp73 regulates GLS2 during in vitro neuronal differentiation elicited by retinoid acid as well as during ex vivo differentiation of primary cortical neurons. The ability to transactivate GLS2 is not unique to TAp73, but, in fact, it is shared by all members of the family. The same authors have very recently reported that p63 regulates GLS2 in an epithelial context, while TAp73 regulates GLS2 in a cancer-related context. Furthermore, the ability of p53 to regulate GLS has been previously reported independently both by the group of Prives and of Levine and Feng. The function of GLS2 is crucial to the life of the cell, as the glutamate produced by GLS2 can be converted to α-ketoglutarate, which is a TCA intermediate; GLS2 activity, therefore, increases ATP production and oxygen consumption. GLS2-produced glutamate can also support the formation of 2 major intracellular scavangers of reactive oxygen species, glutathione (GSH) and NADPH, hence regulating the cellular redox balance. GLS2, controlling the steady-state levels of glutamine/glutamate, activates the transcription factor ATF4, which directly affects serine biosynthesis. Therefore, TAp73, indirectly stimulates the serine pathway, which is highly important in cancer progression,, as serine represents a precursor for macromolecules, such as nucleotides, amino acids, lipids, GSH, and other aminoacids, including glycine in the reaction catalyzed by SerineHydroxyMethylTransferase (SHMT), thus sustaining proliferation of cancer cells. Serine also acts as an allosteric activator of the pyruvate kinase M2 isoform (PKM2), which is predominantly expressed in cancer cells; PKM2 expression is associated with aerobic glycolysis and conversion of pyruvate into lactate. The indirect positive effect of TAp73 on the serine biosynthesis, where serine activates the activity of PKM2, synergizes with the regulation on G6PD in activating the pentose phosphate pathway, as reported by Du et al. In doing so, TAp73 regulates a metabolic response to counteract senescence and aging, as reported for the TAp73-knockout mice. Figure 1 shows the metabolic effects of TAp73 on glutaminolysis, the pentose phosphate pathway, as well as on mitochondrial metabolism.

Figure 1. Regulation of metabolism by TAp73. Representation of p73-regulated pathways. Different pathways are circled in light blue: (1) glycolysis, (2) glutamine anaplerosis, (3) serine biosynthesis, (4) amino acid deprivation. The metabolic effects of TAp73 are shown in light yellow. Relevant enzymes are shown in blue: PHGDH; phosphoglycerate dehydrogenase; PSAT-1, phospho-serine aminotransferase 1; PSPH, phospho-serine-phosphatase; PKM2, pyruvate-kinaseM2; G6PD, glucose-6-phosphate-deydrogenase; Cos4i1, cytochrome C oxidasesubunit4; GLS2, glutaminase2.

The GLS2 promoter is clearly very complex, with distinct subtle effects on different cell types. Accordingly, the fact that TAp73, and the p53 family, is able to regulate GLS2 is surprising. On this regard, the work by Velletri et al. is inserted in a wider scenario, indicating that the p53 family members, and, in particular, TAp73, play a role in maintaining normal metabolism during neuronal differentiation as well as in cancer metabolism.