Biochemical and Biophysical Research Communications
Metabolic pathways regulated by p63
Section snippets
p63 gene structure and function
The p63 gene is expressed as multiple proteins. Indeed, two independent promoters generate transcripts encoding the two major classes of isoforms: the full length TAp63 and the amino-deleted ΔNp63 [1], [2], [3]. TAp63 contains an N-terminal transactivation (TA) domain, whereas ΔNp63 lacks this domain but is still transcriptionally active [4], [5], [6]. At the C-terminal end, alternative splicing generates additional isoforms with different C-termini, named alpha, beta and gamma isoforms [7].
Cancer development
The exact role of TAp63 and deltaNp63 in cancer remains controversial, with both tumour suppressive and oncogenic roles attributed. The ΔNp63 protein is overexpressed in many tumours, particularly squamous cell carcinoma of the skin and lungs. However, ΔNp63 expression is lost during the development of adenocarcinoma of the prostate and breast; this suggests that p63 is a marker of non-invasive epithelial tumours [5], [18], [19], [20]. On the other hand, the contribution of TAp63 protein in vivo
Glucose metabolism
Both p63 isoforms directly affect glucose metabolism, although they have been studied in different biological contexts (Fig. 1) [23]. ΔNp63 plays a pivotal role to sustain proliferative potential of epithelial cells, including keratinocytes, regulating a subset of genes involved in cell cycle and adhesion. Recently, is has been demonstrated that the transcription of hexokinase 2 (HK2), the glycolytic enzyme controlling the first step of glucose utilization, is strongly dependent on p63
Lipid metabolism
The isoform specific TAp63-null mice, surprisingly, showed that TAp63 is important for lipid metabolism, as TAp63 loss resulted in obesity, at 8 months of age, and diabetes [17]. TAp63-null mice are glucose intolerant and insulin resistant, at 5 months of age they show levels of cholesterol, triglycerids, adiponectin, and leptin significantly higher as compared with wild-type mice. TAp63-null mice develop also liver steatosis. Alteration of the mRNA levels of fatty acid synthase and carnitine
Anti-oxidant defense
Similarly to p53, TAp63 activates both pro-oxidant as well as anti-oxidant genes depending on cellular context (Fig. 1). For instance, TAp63 by inducing directly GLS2, protects keratinocytes and H1299 lung adenocarcinoma cells from reactive oxygen species (ROS)-induced apoptosis [25]. Indeed, GLS2 by converting glutamine to glutamate, besides stimulating the formation of α−chetoglutarate and ATP production, can also support the production of two major scavengers of cellular ROS, glutathione and
p63-dependent metabolic pathways
Metabolomic studies performed in p53-null osteosarcoma Tet-On Saos-2 cell line, in which TAp63 expression is dependent on doxycycline addition, partially confirmed that TAp63 contributes to glucose and lipid metabolism (Fig. 2). Double 13C-glucose and 13C15N-glutamine metabolic labeling confirmed that TAp63 causes a large series of metabolic modulations. Expression of TAp63 causes modulation of glycolysis, pentose phosphate pathway, nucleotide biosynthesis. Enhancement of glycolysis and pentose
Conclusion
The transcription factor p63 belongs to the p53-family [33], [34], [35], [36], [37], [38], [39], [40]. Like p53, both TAp63 and TAp73 isoforms have been implicated in tumour suppressor and protection from metastasis [34], [35], [36], [37], [38], [39], [40], [41], [42], [43]. While ΔNp63 has an oncogenic role in specific tumours (skin and lung squamous cell carcinomas), its expression is essential for limb formation and epidermal morphogenesis [2], [44], [45]. Here, we highlight the role of p63
Conflict of interest
The authors state no conflict of interest.
Acknowledgments
This work was supported by Medical Research Council (UK), AIRC 5xmille MCO9979, AIRC Grant IG15653 (to GM) and RC IDI-IRCCS (to GM). Also, partially supported by Fondazione Roma malattie Non trasmissibili Cronico-Degenerative Grant NCDS-2013-00000334 (to GM and EC).
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