Inhibition of cell division by the human cytomegalovirus IE86 protein: role of the p53 pathway or cyclin-dependent kinase 1/cyclin B1.
The human cytomegalovirus (HCMV) IE86 protein induces the human fibroblast cell cycle from G(0)/G(1) to G(1)/S, where cell cycle progression stops. Cells with a wild-type, mutated, or null p53 or cells with null p21 protein were transduced with replication-deficient adenoviruses expressing HCMV IE86 protein or cellular p53 or p21. Even though S-phase genes were activated in a p53 wild-type cell, IE86 protein also induced phospho-Ser(15) p53 and p21 independent of p14ARF but dependent on ATM kinase. These cells did not enter the S phase. In human p53 mutant, p53 null, or p21 null cells, IE86 protein did not up-regulate p21, cellular DNA synthesis was not inhibited, but cell division was inhibited. Cells accumulated in the G(2)/M phase, and there was increased cyclin-dependent kinase 1/cyclin B1 activity. Although the HCMV IE86 protein increases cellular E2F activity, it also blocks cell division in both p53(+/+) and p53(-/-) cells.
Song
Yoon-Jae
YJ
Department of Microbiology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
Stinski
Mark F
MF
D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D003587:Cytomegalovirus / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000494:pharmacology*; D015534:Trans-Activators / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D018844:Cyclin-Dependent Kinases