Direct activation of cyclin-dependent kinase 2 by human papillomavirus E7.

Addition of human papillomavirus (HPV) E7 CDK2/cyclin A or CDK2/cyclin E, purified from either insect cells or bacteria, dramatically upregulates histone H1 kinase activity. Activation is substrate specific, with a smaller effect noted for retinoblastoma protein (Rb). The CDK2 stimulatory activity is equivalent in high-risk (HPV type 16 [HPV16] and ...
HPV31) and low-risk (HPV6b) E7. Mutational analyses of HPV16 E7 indicate that the major activity resides in amino acids 9 to 38, spanning CR1 and CR2, and does not require casein kinase II or Rb-binding domain functions. Synthetic peptides spanning HPV16 amino acid residues 9 to 38 also activate CDK2. Peptides containing this sequence that carry biotin on the carboxy terminus, as well as a photoactivated cross-linking group (benzophenone), also activate the complex and covalently associate with the CDK2/cyclin A complex in a specific manner requiring UV. Cross-linking studies that use protein monomers detect association of the E7 peptides with cyclin A but not CDK2. Together, our results indicate a novel mechanism whereby E7 promotes HPV replication by directly altering CDK2 activity and substrate specificity.
Mesh Terms:
Amino Acid Sequence, CDC2-CDC28 Kinases, Cyclin A, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, Enzyme Activation, Molecular Sequence Data, Oncogene Proteins, Viral, Papillomavirus E7 Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Substrate Specificity, Virus Replication
J. Virol.
Date: Oct. 01, 2003
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