A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

J Biol Chem. 2016 Dec 9;291(50):26138-26150. doi: 10.1074/jbc.M116.737056. Epub 2016 Nov 3.

Abstract

The pyruvate kinase (PK) is a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate, yielding one molecule of ATP. The M2 isoform of PK (PKM2) is predominantly expressed in normal proliferating cells and tumors, and both metabolic and non-metabolic activities for the enzyme in promoting tumor cell proliferation have been identified. However, the exact roles of PKM2 in tumor initiation, growth and maintenance are not yet fully understood. Using immunoprecipitation-coupled LC-MS/MS in MCF7 cells exposed to DNA-damaging agent, we report that the nuclear PKM2 interacts directly with P53 protein, a critical safeguard for genome stability. Specifically, PKM2 inhibits P53-dependent transactivation of the P21 gene by preventing P53 binding to the P21 promoter, leading to a nonstop G1 phase. As a result, PKM2 expression provides a growth advantage for tumor cells in the presence of a DNA damage stimulus. In addition, PKM2 interferes with phosphorylation of P53 at serine 15, known to stimulate P53 activity by the ATM serine/threonine kinase. These findings reveal a new role for PKM2 in modulating the DNA damage response and illustrate a novel mechanism of PKM2 participating in tumorigenesis.

Keywords: DNA damage; DNA damage response; p53; pyruvate kinase; transcription corepressor.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • DNA Damage*
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MCF-7 Cells
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Pyruvate Kinase / genetics
  • Pyruvate Kinase / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Pyruvate Kinase
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins