title: Molecular basis for viral selective replication in cancer cells: activation of CDK2 by adenovirus-induced cyclin E.
abstract: Adenoviruses (Ads) with deletion of E1b55K preferentially replicate in cancer cells and have been used in cancer therapies. We have previously shown that Ad E1B55K protein is involved in induction of cyclin E for Ad replication, but this E1B55K function is not required in cancer cells in which deregulation of cyclin E is frequently observed. In this study, we investigated the interaction of cyclin E and CDK2 in Ad-infected cells. Ad infection significantly increased the large form of cyclin E (cyclin EL), promoted cyclin E/CDK2 complex formation and increased CDK2 phosphorylation at the T160 site. Activated CDK2 caused pRb phosphorylation at the S612 site. Repression of CDK2 activity with the chemical inhibitor roscovitine or with specific small interfering RNAs significantly decreased pRb phosphorylation, with concomitant repression of viral replication. Our results suggest that Ad-induced cyclin E activates CDK2 that targets the transcriptional repressor pRb to generate a cellular environment for viral productive replication. This study reveals a new molecular basis for oncolytic replication of E1b-deleted Ads and will aid in the development of new strategies for Ad oncolytic virotherapies.
authors: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
authors: Pei-Hsin
authors: PH
authors: Cheng
authors: Xiao-Mei
authors: XM
authors: Rao
authors: Kelly M
authors: KM
authors: McMasters
authors: Heshan Sam
authors: HS
authors: Zhou
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D015513:Oncogene Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077546:Roscovitine; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; C553319:E1B55K protein, adenovirus; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D014764:Viral Proteins; D000077546:Roscovitine; D049452:Green Fluorescent Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2