Role of c-myc regulation in Zta-mediated induction of the cyclin-dependentkinase inhibitors p21 and p27 and cell growth arrest

Latency-associated Epstein-Barr virus (EBV) gene expression induces cell pr oliferation. Unlike the latency associated genes, lytic gene expression in EBV, as well as other herpesviruses, elicits cell cycle arrest. Previous st udies have shown that the EBV immediate early lytic transactivator, Zta, in duces a G(0)/G(1) cell cycle arrest through induction of the cyclin-depende nt kinase inhibitors, p21 and p27. Here we show that while EBV latency is i ntimately linked to activation of the protooncogene, c-myc, Zta represses c -myc expression. We also show that inhibition of c-myc expression is requir ed for Zta-mediated growth arrest and for maximal induction of p21 and p27. Nevertheless, induction of p21 and p27 is also influenced by a c-myc-indep endent mechanism. A detailed genetic analysis of Zta's basic/DNA binding re gion identified two distinct subregions that contribute to full induction o f p21 and p27. One subdomain influences p21 and p27 expression through the c-myc-dependent mechanism and the other subdomain influences p21 and p27 in duction through the c-myc-independent pathway. Together, these studies furt her our understanding of the complex nature of Zta-induced growth arrest. ( C) 2001 Academic Press.