GRIM-19 and p16(INK4a) synergistically regulate cell cycle progression and E2F1-responsive gene expression

J Biol Chem. 2010 Sep 3;285(36):27545-52. doi: 10.1074/jbc.M110.105767. Epub 2010 Jun 3.

Abstract

GRIM-19 (Gene associated with Retinoid-IFN-induced Mortality-19) was originally isolated as a growth suppressor in a genome-wide knockdown screen with antisense libraries. Like classical tumor suppressors, mutations, and/or loss of GRIM-19 expression occur in primary human tumors; and it is inactivated by viral gene products. Our search for potential GRIM-19-binding proteins, using mass spectrometry, that permit its antitumor actions led to the inhibitor of cyclin-dependent kinase 4, CDKN2A. The GRIM-19/CDKN2A synergistically suppressed cell cycle progression via inhibiting E2F1-driven gene expression. The N terminus of GRIM-19 and the fourth ankyrin repeat of CDKN2A are crucial for their interaction. The biological relevance of these interactions is underscored by observations that GRIM-19 promotes the inhibitory effect of CDKN2A on CDK4; and mutations from primary tumors disrupt its ability to interact with GRIM-19 and suppress E2F1-driven gene expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Ankyrin Repeat
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Cycle*
  • Cell Line, Tumor
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / chemistry
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • E2F1 Transcription Factor / metabolism*
  • G1 Phase
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation
  • NADH, NADPH Oxidoreductases / chemistry
  • NADH, NADPH Oxidoreductases / deficiency
  • NADH, NADPH Oxidoreductases / genetics
  • NADH, NADPH Oxidoreductases / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Structure, Tertiary

Substances

  • Apoptosis Regulatory Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • E2F1 Transcription Factor
  • Cyclin D1
  • NADH, NADPH Oxidoreductases
  • NDUFA13 protein, human
  • Cyclin-Dependent Kinase 4