P107 USES A P21(CIP1)-RELATED DOMAIN TO BIND CYCLIN CDK2 AND REGULATEINTERACTIONS 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 p5 7, with these complexes. In this report we demonstrate that the pRB-re lated 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/cdk 2 rely on a structurally and functionally related interaction domain. Furthermore, interactions between p107 or p21 with cyclin/cdk2, comple xes are mutually exclusive. In cells treated with DNA-damaging agents elevated levels of p21 cause a dissociation of p107/cyclin/cdk2 comple xes to yield p21/cyclin/cdk2 complexes. finally, the consequences of c yclin/cdk2 interactions with p107 have been examined. The activation o f the p107-bound cyclin/cdk kinases leads to dissociation of p107 from the transcription factor E2F. Together, these results suggest that cy clin/cdk complexes can be regulated by protein molecules from differen t families in a mutually exclusive manner in response to certain signa ls and that these inhibitory proteins may have a potential role in reg ulating macromolecular assembly.