The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors.
While oncoproteins encoded by small DNA tumor viruses and Epstein-Barr virus (EBV) latent antigens facilitate G1/S progression, the EBV lytic switch transactivator Zta was found to inhibit growth by causing cell cycle arrest in G0/G1 in several epithelial tumor cell lines. Expression of Zta results in induction of the tumor suppressor protein, p53, and the cyclin-dependent kinase inhibitors, p21 and p27, as well as accumulation of hypophosphorylated pRb. Up-regulation of p53 and p27 occurs by post-transcriptional mechanisms while expression of p21 is induced at the RNA level in a p53-dependent manner. Inactivation of pRb by transient overexpression of the human papillomavirus E7 oncoprotein indicates that pRb or pRb-related proteins are key mediators of the growth-inhibitory function of Zta. These findings suggest that EBV plays an active role in redirecting epithelial cell physiology to facilitate the viral replicative program through a Zta-mediated growth arrest function.
Cayrol
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Division of Tumor Virology, Division of Neoplastic Disease Mechanisms, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Flemington
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D002453:Cell Cycle; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology*; D006131:Growth Inhibitors; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D016350:Leucine Zippers; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009303:Nasopharyngeal Neoplasms / Q000473:pathology; D016160:Retinoblastoma Protein / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
C063676:BZLF1 protein, Herpesvirus 4, Human; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D008869:Microtubule-Associated Proteins; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D018844:Cyclin-Dependent Kinases