p107 uses a p21CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F.
The kinase activities of the cyclin/cdk complexes can be regulated in a number of ways. The most recently discovered mechanism of regulation is the association of cdk inhibitors (CKIs), such as p21, p27, and p57, with these complexes. In this report we demonstrate that the pRB-related protein p107, like the p21 family of cdk inhibitors, can inhibit the phosphorylation of target substrates by cyclin A/cdk2 and cyclin E/cdk2 complexes, and the associations of p107 and p21 with cyclin/cdk2 rely on a structurally and functionally related interaction domain. Furthermore, interactions between p107 or p21 with cyclin/cdk2 complexes are mutually exclusive. In cells treated with DNA-damaging agents elevated levels of p21 cause a dissociation of p107/cyclin/cdk2 complexes to yield p21/cyclin/cdk2 complexes. Finally, the consequences of cyclin/cdk2 interactions with p107 have been examined. The activation of the p107-bound cyclin/cdk kinases leads to dissociation of p107 from the transcription factor E2F. Together, these results suggest that cyclin/cdk complexes can be regulated by protein molecules from different families in a mutually exclusive manner in response to certain signals and that these inhibitory proteins may have a potential role in regulating macromolecular assembly.
Zhu
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L
Massachusetts General Hospital (MGH) Cancer Center, Charlestown 02129, USA.
Harlow
E
E
Dynlacht
B D
BD
D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D056465:Retinoblastoma-Binding Protein 1; D050720:Retinoblastoma-Like Protein p107; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; C493844:RBL1 protein, human; D056465:Retinoblastoma-Binding Protein 1; D050720:Retinoblastoma-Like Protein p107; D050680:Transcription Factor DP1; D014157:Transcription Factors; D004247:DNA; D018844:Cyclin-Dependent Kinases