Epstein-Barr virus nuclear antigen 2 retards cell growth, induces p21(WAF1) expression, and modulates p53 activity post-translationally

The Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) has been shown to be required for promotion of cell-cycle progression in EBV-immortalized B-lym phocytes. However, other studies have indicated that EBNA2 alone, in the ab sence of other EBV genes, may retard cell growth. To resolve this discrepan cy, we investigated the effect of EBNA2 on the growth of various cells, inc luding EBV target nasopharyngeal carcinoma cells, NPC-TWO1 and NPC-TW04. We found that EBNA2 could retard cell, growth, in stable Vero, HEp-2, and U20 S cell clones expressing EBNA2 and in Vero, 293, NPC-TWO1, and NPC-TW04 cel ls transiently transfected with EBNA2. While investigating the mechanism un derlying the growth-retarding function of EBNA2, we found that EBNA2 induce d p21(WAF1) expression in these cells, This induction of p21(WAF1) expressi on was mediated through p53. EBNA2 was found to stimulate p53 to bind to th e p53-response element within the p21(WAF1) promoter, possibly by promoting p53 phosphorylation. This enhancement of p53 sequence-specific DNA-binding activity may be the mechanism through which EBNA2 activates the expression of p53-regulated genes, including p21(WAF1) and mdm-2. Together, these stu dies reveal a possible intrinsic function of EBNA2 in cell-growth regulatio n and elucidate a novel mechanism by which EBNA2 modulates transcription. ( C) 2000 Academic Press.