PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2)

Curr Biol. 2001 Feb 20;11(4):263-7. doi: 10.1016/s0960-9822(01)00065-3.

Abstract

The PTEN tumor suppressor acts as a phosphatase for phosphatidylinositol-3,4,5-trisphosphate (PIP3) [1, 2]. We have shown previously that PTEN negatively controls the G1/S cell cycle transition and regulates the levels of p27(KIP1), a CDK inhibitor [3, 4]. Recently, we and others have identified an ubiquitin E3 ligase, the SCF(SKP2) complex, that mediates p27 ubiquitin-dependent proteolysis [5-7]. Here we report that PTEN and the PI 3-kinase pathway regulate p27 protein stability. PTEN-deficiency in mouse embryonic stem (ES) cells causes a decrease of p27 levels with concomitant increase of SKP2, a key component of the SCF(SKP2) complex. Conversely, in human glioblastoma cells, ectopic PTEN expression leads to p27 accumulation, which is accompanied by a reduction of SKP2. We found that ectopic expression of SKP2 alone is sufficient to reverse PTEN-induced p27 accumulation, restore the kinase activity of cyclin E/CDK2, and partially overcome the PTEN-induced G1 cell cycle arrest. Consistently, recombinant SCF(SKP2) complex or SKP2 protein alone can rescue the defect in p27 ubiquitination in extracts prepared from cells treated with a PI 3-kinase inhibitor. Our findings suggest that SKP2 functions as a critical component in the PTEN/PI 3-kinase pathway for the regulation of p27(KIP1) and cell proliferation.

Publication types

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

MeSH terms

  • Animals
  • CDC2-CDC28 Kinases*
  • Cell Cycle Proteins*
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / metabolism
  • Genes, Tumor Suppressor*
  • Humans
  • Ligases / genetics
  • Ligases / metabolism*
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • PTEN Phosphohydrolase
  • Peptide Synthases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • SKP Cullin F-Box Protein Ligases
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*
  • Ubiquitin-Protein Ligases
  • Ubiquitins / metabolism*

Substances

  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Cyclin E
  • Microtubule-Associated Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Tumor Suppressor Proteins
  • Ubiquitins
  • Cyclin-Dependent Kinase Inhibitor p27
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Ligases
  • Peptide Synthases