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Papers In Press, published online ahead of print May 2, 2002
Institute of Cancer Biology, Danish Cancer Society, Copenhagen 2100
Corresponding Author: KHH{at}biobase.dk
The ‘pocket proteins’ pRb (retinoblastoma tumor suppressor protein), p107 and p130 regulate cell proliferation via phosphorylation-sensitive interactions with E2F transcription factors and other proteins. We previously identified 22 in vivo phosphorylation sites in human p130, including three sites selectively targeted by cyclin D/Cdk4(6) kinases. Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr369/Ser650/Ser964). In U-2-OS cells, the triple p107*Cdk4* mutant strongly inhibited E2F-4 activity and imposed a G1 arrest resistant to cyclin D1 coexpression. In contrast, the p130*Cdk4 mutant still responded to cyclin D1, suggesting the existence of additional phosphorylation sites critical for E2F-4 regulation. Extensive mutagenesis, sensitive E2F reporter assays and cell cycle analyses allowed identification of six such residues (serines 413, 639, 662, 1044, 1080, 1112) that in addition to the Cdk4-specific sites, are necessary and sufficient for the regulation of E2F-4 and the cell cycle by p130. Surprisingly, twelve of the in vivo phosphorylation sites seem dispensable for E2F regulation, and likely modulate other functions of p130. These results further elucidate the complex regulation of p130, and provide a molecular mechanism to explain the differential control of p107 and p130 by cyclin-dependent kinases.
J. Biol. Chem, 10.1074/jbc.M200381200
Submitted on January 14, 2002
Revised on April 29, 2002
Accepted on May 2, 2002
Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4
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