viral and cell cycle–regulated kinases in cytomegalovirus-induced pseudomitosis and replication病毒和细胞cycle-regulated激酶cytomegalovirus-induced pseudomitosis和复制.pdfVIP

Viral and Cell Cycle–Regulated Kinases in Cytomegalovirus-Induced Pseudomitosis and Replication 1 2 3* Laura Hertel , Sunwen Chou , Edward S. Mocarski 1 Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada, 2 VA Medical Center, Portland, Oregon, United States of America, 3 Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America A process of pseudomitosis occurs during human cytomegalovirus infection that appears similar to cellular mitosis but involves the formation of multiple spindle poles, abnormal condensation, and mislocalization of chromosomal DNA. The relationship of this process to viral replication and cell cycle regulation during infection has been poorly understood. Pseudomitosis consistently peaks at late times of infection in all viral strains examined but at overall highest frequencies (30% to 35% of cells) using one common laboratory strain variant (AD169varATCC). Cyclin- dependent kinase 1 (Cdk1) plays a crucial role in pseudomitosis, mirroring its role in conventional mitosis. Dominant negative Cdk1 inhibits and wild-type Cdk1 stimulates this process; however, viral yields remain the same regardless of pseudomitosis levels. Broad inhibition of cell cycleregulated kinases (Cdk1/Cdk2/Cdk5/Cdk9) with indirubin-39- monoxime substantially decreases viral yields and synergizes with the viral UL97 kinase inhibitor, maribavir. Thus, Cdk1 is necessary and sufficient to drive pseudomitosis, whereas a combination of viral and cell cycleregulated kinases is important during viral replication. Citation: Hertel L, Chou S, Mocarski ES (2007) Viral and cell cycle–regulated kinases in cytomegalovirus-induced ps