Control of E2F activity by p21(Waf1/Cip1)

Cyclin-dependent kinase inhibitors (cdkis), such as p21, are believed to co ntrol proliferation through an ability to function as stoichiometric antago nists of cyclin-dependent kinases (cdks). The p21 gene is a direct transcri ptional target for the p53 protein, and its activation is likely to be impo rtant in effecting the p53 response, It is widely accepted that p21 can inf luence cell cycle progression by controlling the activity of cdks that act on the retinoblastoma tumour suppressor protein (pRb) which, in a hypophosp horylated state, associates with E2F transcription factors to prevent the a ctivation of genes required for progression into S phase, Phosphorylation o f pRb by G1 cdk complexes releases E2F and thereby enables progress through the cell cycle, Here, we describe results which suggest a p21-dependent me chanism that facilitates the regulation of E2F through a pathway that is in dependent of the cdk control of pRb activity. As p21 can associate with E2F subunits, it is possible that these effects are exerted through a complex with E2F. Furthermore, we find that p21 can regulate transcription in vitro . The results suggest that p21 may control E2F activity through a pathway t hat acts independently of pRb.