HUMAN PAPILLOMAVIRUS E7 ONCOPROTEINS BIND A SINGLE FORM OF CYCLIN-E IN A COMPLEX WITH CDK2 AND P107

The E6 and E7 proteins of the high-risk human papillomaviruses (HPVs) act coordinately to immortalize human keratinocytes. These viral oncop roteins function by binding and altering the activity of cellular prot eins which regulate cell cycle progression. Among the proteins bound b y E7 are the retinoblastoma protein, Rb, as well as the related p107 a nd p130 proteins. In addition, E7 binds cyclin A, which regulates tran sit through the S and G2/M phases of the cell cycle. In this study, we demonstrate that HPV 18 E7 also associates with cyclin E which contro ls the G1/S transition. E7/cyclin E complexes were immunoprecipitated from E7-expressing cells as well as from cell extracts using GST-E7 fu sion proteins. E7 was found to complex with a single form of cyclin E, and the binding was mediated through p107. Both E7/cyclin E and E7/cy clin A complexes exhibit kinase activity through associated cdk2 prote ins which can contribute to phosphorylation of p107. The association o f E7 with proteins which regulate transit through the cell cycle may p rovide an additional mechanism by which infection with human papilloma viruses results in cellular hyperproliferation. (C) 1996 Academic Pres s, Inc.