P63 regulates glutaminase 2 expression

Arianna Giacobbe, Lucilla Bongiorno-Borbone, Francesca Bernassola, Alessandro Terrinoni, Elke Katrin Markert, Arnold J. Levine, Zhaohui Feng, Massimilano Agostini, Lello Zolla, Alessandro Finazzi Agrò, Daniel A. Notterman, Gerry Melino, Angelo Peschiaroli

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

The transcription factor p63 is critical for many biological processes, including development and maintenance of epidermal tissues and tumorigenesis. Here, we report that the TAp63 isoforms regulate cell metabolism through the induction of the mitochondrial glutaminase 2 (GLS2) gene both in primary cells and tumor cell lines. By ChIP analysis and luciferase assay, we confirmed that TAp63 binds directly to the p53/p63 consensus DNA binding sequence within the GLS2 promoter region. Given the critical role of p63 in epidermal differentiation, we have investigated the regulation of GLS2 expression during this process. GLS2 and TAp63 expression increases during the in vitro differentiation of primary human keratinocytes, and depletion of GLS2 inhibits skin differentiation both at molecular and cellular levels. We found that GLS2 and TAp63 expression are concomitantly induced in cancer cells exposed to oxidative stresses. siRNA-mediated depletion of GLS2 sensitizes cells to ROS-induced apoptosis, suggesting that the TAp63/GLS2 axis can be functionally important as a cellular antioxidant pathway in the absence of p53. Accordingly, we found that GLS2 is upregulated in colon adenocarcinoma. Altogether, our findings demonstrate that GLS2 is a bona fide TAp63 target gene, and that the TAp63-dependent regulation of GLS2 is important for both physiological and pathological processes.

Original languageEnglish (US)
Pages (from-to)1395-1405
Number of pages11
JournalCell Cycle
Volume12
Issue number9
DOIs
StatePublished - May 1 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Keywords

  • Colon carcinoma
  • Glutaminolysis
  • P63
  • Skin differentiation

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  • Cite this

    Giacobbe, A., Bongiorno-Borbone, L., Bernassola, F., Terrinoni, A., Markert, E. K., Levine, A. J., Feng, Z., Agostini, M., Zolla, L., Agrò, A. F., Notterman, D. A., Melino, G., & Peschiaroli, A. (2013). P63 regulates glutaminase 2 expression. Cell Cycle, 12(9), 1395-1405. https://doi.org/10.4161/cc.24478