title: NAD+ modulates p53 DNA binding specificity and function.
abstract: DNA damage induces p53 DNA binding activity, which affects tumorigenesis, tumor responses to therapies, and the toxicities of cancer therapies (B. Vogelstein, D. Lane, and A. J. Levine, Nature 408:307-310, 2000; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2:594-604, 2002). Both transcriptional and transcription-independent activities of p53 contribute to DNA damage-induced cell cycle arrest, apoptosis, and aneuploidy prevention (M. B. Kastan et al., Cell 71:587-597, 1992; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2:594-604, 2002). Small-molecule manipulation of p53 DNA binding activity has been an elusive goal, but here we show that NAD(+) binds to p53 tetramers, induces a conformational change, and modulates p53 DNA binding specificity in vitro. Niacinamide (vitamin B(3)) increases the rate of intracellular NAD(+) synthesis, alters radiation-induced p53 DNA binding specificity, and modulates activation of a subset of p53 transcriptional targets. These effects are likely due to a direct effect of NAD(+) on p53, as a molecule structurally related to part of NAD(+), TDP, also inhibits p53 DNA binding, and the TDP precursor, thiamine (vitamin B(1)), inhibits intracellular p53 activity. Niacinamide and thiamine affect two p53-regulated cellular responses to ionizing radiation: rereplication and apoptosis. Thus, niacinamide and thiamine form a novel basis for the development of small molecules that affect p53 function in vivo, and these results suggest that changes in cellular energy metabolism may regulate p53.
authors.affiliation: Department of Hematology-Oncology, St. Jude Children's Research Hospital, Room D-5048, 332 N. Lauderdale St., Memphis, TN 38105-2794, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: McLure
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000494:pharmacology*; D009536:Niacinamide / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013831:Thiamine / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D009243:NAD; D009536:Niacinamide; D000244:Adenosine Diphosphate; D004247:DNA; D013831:Thiamine