Genetic dissection of cell growth arrest functions mediated by the
epstein-barr virus lytic gene product, Zta.
Rodriguez A, Armstrong M, Dwyer D, Flemington E
Harvard University and Dana-Farber Cancer Institute, Boston, Massachusetts
02115, USA.
J Virol 1999 Nov;73(11):9029-38
Abstract
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.