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The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2).

Genes & development | Nov 15, 2002

p130 is a tumor suppressor of the pocket protein family whose expression is posttranscriptionally regulated and largely G0 restricted. The mechanism of down-regulation of p130 expression in proliferating cells was investigated. Our results indicate that the decline of p130 expression as G0 cells reenter the cell cycle is due to a decrease in protein stability. The enhancement of p130 turnover in late G1 and S phase compared with G0 and early G1 phase was dependent on Cdk4/6-specific phosphorylation of p130 on Serine 672, and independent of Cdk2 activity. The activity of the ubiquitin ligase complex Skp1-Cul1/Cdc53-F-box protein Skp2 (SCF(Skp2)) and the proteasome were necessary for p130 degradation. In vitro, recombinant Skp2 was able to bind hyperphosphorylated but not dephosphorylated p130. Furthermore, in vitro polyubiquitination of p130 by SCF(Skp2) was specifically dependent on phosphorylation of p130 on Serine 672. Thus, like the Cdk inhibitor p27(Kip1), p130 turnover is regulated by Cdk-dependent G1 phosphorylation leading to ubiquitin-dependent proteolysis.

Pubmed ID: 12435635 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | CDC2-CDC28 Kinases | Cell Cycle | Cell Cycle Proteins | Cells, Cultured | Cyclin-Dependent Kinase 2 | Cyclin-Dependent Kinase 4 | Cyclin-Dependent Kinase 6 | Cyclin-Dependent Kinases | Cysteine Endopeptidases | Fungal Proteins | Humans | Ligases | Multienzyme Complexes | Phosphoproteins | Phosphorylation | Proteasome Endopeptidase Complex | Protein-Serine-Threonine Kinases | Proteins | Proto-Oncogene Proteins | Retinoblastoma-Like Protein p130 | Saccharomyces cerevisiae Proteins | Serine | Ubiquitin | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA078343
  • Agency: NCI NIH HHS, Id: R56 CA078343
  • Agency: NCI NIH HHS, Id: CA78343

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