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(Received for publication, September 26, 1996)
From the Division of Tumor Virology, Division of Neoplastic Disease
Mechanisms, Dana-Farber Cancer Institute, Harvard Medical School,
Boston, Massachusetts 02115
The Epstein-Barr virus (EBV) immediate early
transactivator Zta is a basic leucine zipper (bZIP) transcription
factor that causes G0/G1 cell cycle arrest
through induction of the tumor suppressor protein, p53, and the
cyclin-dependent kinase inhibitors, p21 and p27 (Cayrol,
C., and Flemington, E. K. (1996) EMBO J. 15, 2748-2759).
Here, we report a genetic analysis of Zta-mediated G0/G1 growth arrest and p21 induction. The
majority of the Zta transactivation domain can be deleted (Z
1-128)
without significantly affecting the ability of Zta to elicit growth
arrest. A larger amino-terminal deletion (Z1-167) abrogates the
ability of Zta to inhibit proliferation, mapping the growth-inhibitory
domain to a carboxyl-terminal region encompassing the bZIP domain
(amino acids 128-245). The integrity of the bZIP domain is required
for growth suppression since a two-amino acid mutant which is defective for homodimerization, fails to induce cell cycle arrest. Western blot
analysis of p21 expression in cells expressing Zta mutants reveals that
the ability of Zta mutants to cause G0/G1
growth arrest is intimately related to their capacity to induce p21
expression. Together, these data demonstrate that a carboxyl-terminal
region of Zta that includes the bZIP domain is sufficient to mediate G0/G1 growth arrest and p21 induction.
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