SCF-mediated Cdh1 degradation defines a negative feedback system that coordinates cell-cycle progression

Cell Rep. 2013 Aug 29;4(4):803-16. doi: 10.1016/j.celrep.2013.07.031. Epub 2013 Aug 22.

Abstract

Proper cell-cycle transitions are driven by waves of ubiquitin-dependent degradation of key regulators by the anaphase-promoting complex (APC) and Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligase complexes. But precisely how APC and SCF activities are coordinated to regulate cell-cycle progression remains largely unclear. We previously showed that APC/Cdh1 earmarks the SCF component Skp2 for degradation. Here, we continue to report that SCF(β-TRCP) reciprocally controls APC/Cdh1 activity by governing Cdh1 ubiquitination and subsequent degradation. Furthermore, we define both cyclin A and Plk1, two well-known Cdh1 substrates, as upstream modifying enzymes that promote Cdh1 phosphorylation to trigger Cdh1 ubiquitination and subsequent degradation by SCF(β-TRCP). Thus, our work reveals a negative repression mechanism for SCF to control APC, thereby illustrating an elegant dual repression system between these two E3 ligase complexes to create the ordered cascade of APC and SCF activities governing timely cell-cycle transitions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome / metabolism
  • Animals
  • Cdh1 Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Cycle*
  • Cyclin A / metabolism
  • Feedback, Physiological*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteolysis*
  • Proto-Oncogene Proteins / metabolism
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Ubiquitination
  • Xenopus

Substances

  • Cdh1 Proteins
  • Cell Cycle Proteins
  • Cyclin A
  • Proto-Oncogene Proteins
  • Anaphase-Promoting Complex-Cyclosome
  • SKP Cullin F-Box Protein Ligases
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1