title: The NAD+ synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) is a p53 downstream target.
abstract: NAD(+) metabolism plays key roles not only in energy production but also in diverse cellular physiology. Aberrant NAD(+) metabolism is considered a hallmark of cancer. Recently, the tumor suppressor p53, a major player in cancer signaling pathways, has been implicated as an important regulator of cellular metabolism. This notion led us to examine whether p53 can regulate NAD(+) biosynthesis in the cell. Our search resulted in the identification of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2), a NAD(+) synthetase, as a novel downstream target gene of p53. We show that NMNAT-2 expression is induced upon DNA damage in a p53-dependent manner. Two putative p53 binding sites were identified within the human NMNAT-2 gene, and both were found to be functional in a p53-dependent manner. Furthermore, knockdown of NMNAT-2 significantly reduces cellular NAD(+) levels and protects cells from p53-dependent cell death upon DNA damage, suggesting an important functional role of NMNAT-2 in p53-mediated signaling. Our demonstration that p53 modulates cellular NAD(+) synthesis is congruent with p53's emerging role as a key regulator of metabolism and related cell fate.
authors.affiliation: Department of Microbiology and Immunology; Dalhousie University; Halifax, Nova Scotia, Canada.
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Pan
authors.affiliation: Department of Microbiology and Immunology; Dalhousie University; Halifax, Nova Scotia, Canada.
authors.forename: Dae-Gyun
authors.initials: DG
authors.lastname: Ahn
authors.affiliation: Department of Microbiology and Immunology; Dalhousie University; Halifax, Nova Scotia, Canada.
authors.forename: Tanveer
authors.initials: T
authors.lastname: Sharif
authors.affiliation: Department of Pathology; Dalhousie University; Halifax, Nova Scotia, Canada.
authors.forename: Derek
authors.initials: D
authors.lastname: Clements
authors.affiliation: Department of Microbiology and Immunology; Dalhousie University; Halifax, Nova Scotia, Canada; Strategy & Organizational Performance; IWK Health Centre; Halifax, Nova Scotia, Canada.
authors.forename: Shashi A
authors.initials: SA
authors.lastname: Gujar
authors.affiliation: Department of Microbiology and Immunology; Dalhousie University; Halifax, Nova Scotia, Canada; Department of Pathology; Dalhousie University; Halifax, Nova Scotia, Canada.
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
mesh_terms: D001665:Binding Sites; D016923:Cell Death; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D009243:NAD / Q000378:metabolism*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D009243:NAD; C484008:NMNAT2 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase
keywords: NAD+ biosynthesis; NMNAT-2; apoptosis; p53