C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4

Mol Cell. 2001 Oct;8(4):817-28. doi: 10.1016/s1097-2765(01)00366-5.

Abstract

The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) is a strong inhibitor of cell proliferation. We found that C/EBPalpha directly interacts with cdk2 and cdk4 and arrests cell proliferation by inhibiting these kinases. We mapped a short growth inhibitory region of C/EBPalpha between amino acids 175 and 187. This portion of C/EBPalpha is responsible for direct inhibition of cyclin-dependent kinases and causes growth arrest in cultured cells. C/EBPalpha inhibits cdk2 activity by blocking the association of cdk2 with cyclins. Importantly, the activities of cdk4 and cdk2 are increased in C/EBPalpha knockout livers, leading to increased proliferation. Our data demonstrate that the liver-specific transcription factor C/EBPalpha brings about growth arrest through direct inhibition of cdk2 and cdk4.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • CDC2-CDC28 Kinases*
  • Cell Division / physiology*
  • Cell Fractionation
  • Cell Line
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / chemistry
  • Cyclin-Dependent Kinases / metabolism*
  • Enzyme Inhibitors / metabolism
  • Genes, Reporter / genetics
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Protein Structure, Secondary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins*
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cdk2 protein, mouse
  • Cdk2 protein, rat
  • Cdk4 protein, mouse
  • Cdk4 protein, rat
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases