Anaphase-promoting complex/cyclosome Participates in the Acute Response to Protein-Damaging Stress

Mol Cell Biol. 2010 Dec;30(24):5608-20. doi: 10.1128/MCB.01506-09. Epub 2010 Oct 11.

Abstract

The ubiquitin E3 ligase anaphase-promoting complex/cyclosome (APC/C) drives degradation of cell cycle regulators in cycling cells by associating with the coactivators Cdc20 and Cdh1. Although a plethora of APC/C substrates have been identified, only a few transcriptional regulators are described as direct targets of APC/C-dependent ubiquitination. Here we show that APC/C, through substrate recognition by both Cdc20 and Cdh1, mediates ubiquitination and degradation of heat shock factor 2 (HSF2), a transcription factor that binds to the Hsp70 promoter. The interaction between HSF2 and the APC/C subunit Cdc27 and coactivator Cdc20 is enhanced by moderate heat stress, and the degradation of HSF2 is induced during the acute phase of the heat shock response, leading to clearance of HSF2 from the Hsp70 promoter. Remarkably, Cdc20 and the proteasome 20S core α2 subunit are recruited to the Hsp70 promoter in a heat shock-inducible manner. Moreover, the heat shock-induced expression of Hsp70 is increased when Cdc20 is silenced by a specific small interfering RNA (siRNA). Our results provide the first evidence for participation of APC/C in the acute response to protein-damaging stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome
  • Antigens, CD
  • Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cdc20 Proteins
  • Cell Cycle / physiology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • HEK293 Cells
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Heat-Shock Response / physiology*
  • Humans
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Stress, Physiological*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligase Complexes / genetics
  • Ubiquitin-Protein Ligase Complexes / metabolism*

Substances

  • Antigens, CD
  • Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
  • CDC27 protein, human
  • CDH1 protein, human
  • Cadherins
  • Cdc20 Proteins
  • Cell Cycle Proteins
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Protein Subunits
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Transcription Factors
  • HSF2 protein, human
  • CDC20 protein, human
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • Proteasome Endopeptidase Complex