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A Skp2 autoinduction loop and restriction point control

Yuval Yung1, Janice L Walker, James M Roberts

  • 1Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

The Journal of Cell Biology
|August 29, 2007
PubMed

Insights

A novel feedback loop autoinduces Skp2 protein during cell cycle G1 progression. This Skp2-mediated degradation of p27 protein is crucial for transitioning to mitogen-independence.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Skp2 (S-phase kinase-associated protein 2) is a key regulator of cell cycle progression.
  • p27(kip1) (p27) is a cyclin-dependent kinase inhibitor that restrains cell cycle progression.
  • The interplay between Skp2 and p27 is critical for cell cycle control.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of Skp2 during G1 phase.
  • To investigate the role of a newly identified feedback loop involving Skp2 and p27.
  • To determine the functional significance of Skp2-dependent p27 degradation in cell cycle progression.

Main Methods:

  • Identification of a conserved E2F site in the Skp2 promoter.
  • Generation of a Skp2-resistant p27 mutant (p27(T187A)).
  • Knockdown of Skp2 in mouse embryonic fibroblasts and HPV-E7 expressing fibroblasts.

Main Results:

  • A self-amplifying feedback loop autoinduces Skp2 during G1 phase, involving p27, cyclin E-CDK2, and Rb.
  • Interference with this loop via p27(T187A) delays passage through the restriction point.
  • Skp2 knockdown inhibits S phase entry in normal fibroblasts but not in HPV-E7 fibroblasts.

Conclusions:

  • The Skp2-p27 autoinduction loop is essential for the transition to mitogen-independence.
  • Skp2-dependent proteolysis of p27 plays a selective role in this transition.
  • Skp2-dependent proteolysis may be dispensable when pocket proteins are constitutively inactivated.

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