title: NAMPT pathway is involved in the FOXO3a-mediated regulation of GADD45A expression.
abstract: Nicotinamide-phosphoribosyltransferase (NAMPT), induced under stress, converts nicotinamide (NA) to nicotinamide mononucleotide (NMN), which then reacts with ATP to regenerate NAD(+). Despite the pivotal role of NAD(+) in metabolic reactions, the molecular pathways triggered by the intracellular changes in NAD(+) level in cancer cells are largely unknown. Growth Arrest and DNA Damage-inducible Gene (GADD45A) is regulated by multiple cellular factors which play an important role in the control of cell-cycle checkpoint, DNA repair process and signal transduction. The present study was designed to assess the significance of intracellular NAD(+) levels on the regulation of GADD45A expression. The results of this study demonstrate an inverse relationship between NAMPT expression and the regulation of GADD45A gene. Thus, an overexpression of NAMPT led to a decreased expression of GADD45A, whereas, the inhibition of NAMPT by the known chemical inhibitor FK866 increased the expression of GADD45A in cells. Inhibition of SIRT1, an NAD(+)-dependent deacetylase, using shRNA also led to an increased expression of GADD45A gene. In further experiments we could show that the increased expression of GADD45A under the above experimental conditions, NAMPT inhibition by FK866, involves acetylation of FOXO3a, a member of the important family of forkhead (FOXO) proteins. This knowledge should contribute to our understanding of the role played by NAMPT and SIRT1 in the regulation of GADD45A expression by FOXO3a.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl Neuberg Str-1, 30625 Hannover, Germany. thakur.basant@mh-hannover.de
authors.forename: Basant Kumar
authors.initials: BK
authors.lastname: Thakur
authors.forename: Yannick
authors.initials: Y
authors.lastname: Lippka
authors.forename: Tino
authors.initials: T
authors.lastname: Dittrich
authors.forename: Prakash
authors.initials: P
authors.lastname: Chandra
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
mesh_terms: D000107:Acetylation; D000178:Acrylamides / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D056564:Sirtuin 1 / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000178:Acrylamides; D018797:Cell Cycle Proteins; D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; D009687:Nuclear Proteins; D010880:Piperidines; D012333:RNA, Messenger; D056564:Sirtuin 1; C499517:FOXO3 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; C085455:nicotinamide phosphoribosyltransferase, human; C447939:SIRT1 protein, human