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NAD+ modulates p53 DNA binding specificity and function.

Publication ,  Journal Article
McLure, KG; Takagi, M; Kastan, MB
Published in: Mol Cell Biol
November 2004

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.

Duke Scholars

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

November 2004

Volume

24

Issue

22

Start / End Page

9958 / 9967

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Thiamine
  • Recombinant Proteins
  • Protein Structure, Quaternary
  • Protein Conformation
  • Protein Binding
  • Niacinamide
  • NAD
  • Mice, Knockout
  • Mice, Inbred C57BL
 

Citation

APA
Chicago
ICMJE
MLA
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McLure, K. G., Takagi, M., & Kastan, M. B. (2004). NAD+ modulates p53 DNA binding specificity and function. Mol Cell Biol, 24(22), 9958–9967. https://doi.org/10.1128/MCB.24.22.9958-9967.2004
McLure, Kevin G., Masatoshi Takagi, and Michael B. Kastan. “NAD+ modulates p53 DNA binding specificity and function.Mol Cell Biol 24, no. 22 (November 2004): 9958–67. https://doi.org/10.1128/MCB.24.22.9958-9967.2004.
McLure KG, Takagi M, Kastan MB. NAD+ modulates p53 DNA binding specificity and function. Mol Cell Biol. 2004 Nov;24(22):9958–67.
McLure, Kevin G., et al. “NAD+ modulates p53 DNA binding specificity and function.Mol Cell Biol, vol. 24, no. 22, Nov. 2004, pp. 9958–67. Pubmed, doi:10.1128/MCB.24.22.9958-9967.2004.
McLure KG, Takagi M, Kastan MB. NAD+ modulates p53 DNA binding specificity and function. Mol Cell Biol. 2004 Nov;24(22):9958–9967.

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

November 2004

Volume

24

Issue

22

Start / End Page

9958 / 9967

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Thiamine
  • Recombinant Proteins
  • Protein Structure, Quaternary
  • Protein Conformation
  • Protein Binding
  • Niacinamide
  • NAD
  • Mice, Knockout
  • Mice, Inbred C57BL