INACTIVATION OF THE CDK INHIBITOR P27(KIP1) BY THE HUMAN PAPILLOMAVIRUS TYPE-16 E7 ONCOPROTEIN

Expression of the E7 oncogene of HPV-16 induces S phase entry of mamma lian cells in the presence of antiproliferative signals. In particular , E7 can bypass G(0)/G(1) arrest in response to both serum withdrawal and loss of cell adhesion, two experimental conditions in which cell c ycle progression is accompanied by elevated levels of the cdk inhibito r p27(KIP1). We show here that E7 can antagonize the ability of p27(KI P1) block cyclin E-associated kinase in vitro and to inhibit transcrip tion from the cyclin A gene in transfection experiments. E7 associates with p27(KIP1) both in a reconstituted in vitro system and in extract s of mammalian cells, and association requires the C-terminal part of E7. The interaction between p27(KIP1) and E7 can also be demonstrated in a yeast two hybrid system. The data suggest that the ability of E7 to override certain forms of G(0)/G(1) arrest is mediated in part by b inding to and subsequent inactivation of the cdk inhibitor p27(KIP1).