Proteasome-dependent degradation of transcription factor activating enhancer-binding protein 4 (TFAP4) controls mitotic division

J Biol Chem. 2014 Mar 14;289(11):7730-7. doi: 10.1074/jbc.M114.549535. Epub 2014 Feb 5.

Abstract

TFAP4, a basic helix-loop-helix transcription factor that regulates the expression of a multitude of genes involved in the regulation of cellular proliferation, stemness, and epithelial-mesenchymal transition, is up-regulated in colorectal cancer and a number of other human malignancies. We have found that, during the G2 phase of the cell division cycle, TFAP4 is targeted for proteasome-dependent degradation by the SCF(βTrCP) ubiquitin ligase. This event requires phosphorylation of TFAP4 on a conserved degron. Expression of a stable TFAP4 mutant unable to interact with βTrCP results in a number of mitotic defects, including chromosome missegregation and multipolar spindles, which eventually lead to the activation of the DNA damage response. Our findings reveal that βTrCP-dependent degradation of TFAP4 is required for the fidelity of mitotic division.

Keywords: BetaTrCP; Cell Cycle; E3 Ubiquitin Ligase; Mitosis; Protein Degradation; TFAP4; Ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Damage
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epithelial-Mesenchymal Transition
  • G2 Phase
  • Gene Expression Regulation*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mass Spectrometry
  • Microscopy, Fluorescence
  • Mitosis*
  • Mutation
  • Phosphorylation
  • Plasmids / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Transcription Factors
  • enhancer-binding protein AP-4
  • SKP Cullin F-Box Protein Ligases
  • Proteasome Endopeptidase Complex