Metabolic pathways regulated by p63

https://doi.org/10.1016/j.bbrc.2016.10.094Get rights and content

Highlights

  • The transcription factor p63 is involved in development and cancer.

  • p63 regulates glucose and lipid metabolism.

  • p63 contributes to anti-oxidant defences.

  • p63 regulates metabolism of cancer cells.

Abstract

The transcription factor p63 belongs to the p53-family and is a master regulator of proliferative potential, lineage specification, and differentiation in epithelia during development and tissue homeostasis. In cancer, p63 contribution is isoform-specific, with both oncogenic and tumour suppressive roles attributed, for ΔNp63 and TAp63, respectively. Recently, p53 and TAp73, in line with other tumour suppressor genes, have emerged as important regulators of energy metabolism and metabolic reprogramming in cancer. To date, p63 contributions in controlling energy metabolism have been partially investigated; given the extensive interaction of the p53 family members, these studies have potential implications in tumour cells for metabolic reprogramming. Here, we review the role of p63 isoforms, TAp63 and ΔNp63, in controlling cell metabolism, focusing on their specific metabolic target genes and their physiological/functional context of action.

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).

References (45)

  • E. Candi et al.

    How the TP53 family proteins TP63 and TP73 contribute to tumorigenesis: regulators and effectors

    Hum. Mutat.

    (2014)
  • T. Rinne et al.

    A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes

    Hum. Mol. Genet.

    (2008)
  • C.P. Crum et al.

    p63 in epithelial survival, germ cell surveillance, and neoplasia

    Annu. Rev. Pathol.

    (2010)
  • A.A. Mills et al.

    p63 is a p53 homologue required for limb and epidermal morphogenesis

    Nature

    (1999)
  • A. Yang et al.

    p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development

    Nature

    (1999)
  • E. Candi et al.

    Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice

    Cell. death. Differ.

    (2006)
  • R.A. Romano et al.

    ΔNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation

    Development

    (2012)
  • O. Gressner et al.

    TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria

    EMBO J.

    (2005)
  • A.J. Levine et al.

    The p53 family: guardians of maternal reproduction

    Nat. Rev. Mol. Cell. Biol.

    (2011)
  • A. Terrinoni et al.

    Role of p63 and the Notch pathway in cochlea development and sensorineural deafness

    Proc. Natl. Acad. Sci. U. S. A.

    (2013)
  • G. Melino

    p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

    Cell. Death Differ.

    (2011)
  • S.M. Rothenberg et al.

    The molecular pathogenesis of head and neck squamous cell carcinoma

    J. Clin. Invest.

    (2012)
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