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The NAD+ synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) is a p53 downstream target

Lu-Zhe Pan1, Dae-Gyun Ahn1, Tanveer Sharif1

  • 1Department of Microbiology and Immunology; Dalhousie University; Halifax, Nova Scotia, Canada.

Cell Cycle (Georgetown, Tex.)
|February 21, 2014
PubMed

Insights

The tumor suppressor p53 regulates cellular metabolism by controlling NAD(+) biosynthesis. P53 targets NMNAT-2, impacting NAD(+) levels and cell death pathways, highlighting p53

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Metabolism

Background:

  • NAD(+) metabolism is crucial for cellular energy and physiology.
  • Dysregulated NAD(+) metabolism is a hallmark of cancer.
  • The tumor suppressor p53 is a key regulator in cancer signaling and metabolism.

Purpose of the Study:

  • To investigate if p53 regulates NAD(+) biosynthesis.
  • To identify downstream targets of p53 involved in NAD(+) metabolism.

Main Methods:

  • Identified nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) as a p53 target gene.
  • Demonstrated p53-dependent induction of NMNAT-2 expression upon DNA damage.
  • Validated functional p53 binding sites within the human NMNAT-2 gene.
  • Assessed the impact of NMNAT-2 knockdown on cellular NAD(+) levels and p53-mediated cell death.

Main Results:

  • NMNAT-2 is a novel downstream target gene of p53.
  • NMNAT-2 expression is induced by DNA damage in a p53-dependent manner.
  • NMNAT-2 knockdown reduces cellular NAD(+) levels and protects cells from p53-dependent death.

Conclusions:

  • p53 modulates cellular NAD(+) synthesis through NMNAT-2.
  • NMNAT-2 plays a functional role in p53-mediated signaling and cell fate.
  • These findings support p53's role as a central regulator of metabolism and cell fate.
Keywords:
NAD+ biosynthesisNMNAT-2apoptosisp53

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