Genetic dissection of cell growth arrest functions mediated by the Epstein-Barr virus lytic gene product, Zta.
Expression of the Epstein-Barr virus (EBV) latency-associated genes activates cell cycle progression and drives immortalization of the infected cell. In contrast, progression of the EBV replication program occurs most efficiently in growth-arrested cells. Previous studies showed that the EBV-encoded immediate-early transcription factor, Zta, can induce expression of the cyclin-dependent kinase inhibitors, p21 and p27, the tumor suppressor, p53, and cell growth arrest. Moreover, Zta-mediated induction of growth arrest occurs independently of its transcriptional transactivation function. Here we show that substitution of Zta's basic DNA binding domain with the analogous region of the Zta homologue, c-Fos, abrogates Zta's ability to induce growth arrest and to induce p21, p27, or p53 expression, suggesting that protein-protein interactions between this region of Zta and key cell cycle control proteins are involved in signaling cell cycle arrest. We also show that despite the crucial role for Zta's basic domain in eliciting cell growth arrest, its amino terminus is required for efficient induction of p27 and it modulates the level of p53 induction. Last, we provide evidence that Zta-mediated inductions of p21, p27, and p53 occur, at least in part, through distinct pathways. Therefore, Zta interacts with multiple growth arrest pathways, a property which may have evolved partly as a means to ensure that lytic replication occurs in a growth-arrested setting in multiple different tissues in various states of differentiation.
Rodriguez
A
A
Harvard University, Boston, Massachusetts 02115, USA.
Armstrong
M
M
Dwyer
D
D
Flemington
E
E
D000595:Amino Acid Sequence; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009124:Muscle Proteins; D015398:Signal Transduction; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014764:Viral Proteins
C063676:BZLF1 protein, Herpesvirus 4, Human; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins