title: p63 regulates glutaminase 2 expression.
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.
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Giacobbe
authors.forename: Lucilla
authors.initials: L
authors.lastname: Bongiorno-Borbone
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernassola
authors.forename: Alessandro
authors.initials: A
authors.lastname: Terrinoni
authors.forename: Elke Katrin
authors.initials: EK
authors.lastname: Markert
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
authors.forename: Massimilano
authors.initials: M
authors.lastname: Agostini
authors.forename: Lello
authors.initials: L
authors.lastname: Zolla
authors.forename: Alessandro Finazzi
authors.initials: AF
authors.lastname: Agrò
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Notterman
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Angelo
authors.initials: A
authors.lastname: Peschiaroli
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D019610:Cytoprotection / Q000187:drug effects; D004249:DNA Damage; D005972:Glutaminase / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000166:cytology; D013312:Stress, Physiological / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D017382:Reactive Oxygen Species; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D005972:Glutaminase
keywords: colon carcinoma; glutaminolysis; p63; skin differentiation