The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors.

Abstract

While oncoproteins encoded by small DNA tumor viruses and Epstein‐Barr virus (EBV) latent antigens facilitate G1/S progression, the EBV lytic switch transactivator Zta was found to inhibit growth by causing cell cycle arrest in G0/G1 in several epithelial tumor cell lines. Expression of Zta results in induction of the tumor suppressor protein, p53, and the cyclin‐dependent kinase inhibitors, p21 and p27, as well as accumulation of hypophosphorylated pRb. Up‐regulation of p53 and p27 occurs by post‐transcriptional mechanisms while expression of p21 is induced at the RNA level in a p53‐dependent manner. Inactivation of pRb by transient overexpression of the human papillomavirus E7 oncoprotein indicates that pRb or pRb‐related proteins are key mediators of the growth‐inhibitory function of Zta. These findings suggest that EBV plays an active role in redirecting epithelial cell physiology to facilitate the viral replicative program through a Zta‐mediated growth arrest function.

Lytic replication-associated protein (RAP) encoded by Kaposi sarcoma-associated herpesvirus causes p21 CIP-1 -mediated G 1 cell cycle arrest through CCAAT/enhancer-binding protein-α

“…Analogous experiments performed with DG-75 lymphoma cells as negative controls revealed no induction of either the C͞EBP␣ or p21 proteins after TPA treatment (data not shown), suggesting that KSHV lytic infection was responsible for the up-regulation of both of these proteins. These results imply that, unlike the EBV lytic cycle trigger protein ZTA (also known as BELF1 or Zebra), which reportedly induces both p21 and p27 protein expression (25), KSHV RAP protein induces G 1 cell cycle arrest only through the p21 pathway.…”

“…The EBV-encoded ZTA lytic transactivator protein also inhibits G 1 to S-phase cell cycle progression in lytically activated lymphoma cells by inducing the expression of the cyclindependent kinase inhibitors, p21 CIP-1 and p27 KIP (25,26). The KSHV-encoded RAP protein is evolutionarily related to ZTA and also contains a leucine zipper dimerization domain, but has no amino acid homology.…”

“…Unlike ZTA, RAP is not known either to bind to DNA or to function as a direct transcriptional activator (4,27). Both RAP and ZTA have been suggested to interact with and stabilize p53 (25,28), but ZTA can also induce p21 expression through an unknown p53-independent pathway. Furthermore, RAP up-regulates the human p21 gene promoter in reporter gene assays only when cotransfected with C͞EBP␣ and still does so in the Hep3B cell line lacking p53 [F.Y.W., Q.T., H.C., C.A.R., S. Wang, C.F., G. Liao, M.F., C. Chiou, J.C., et al The strong inhibition of G 1 to S cell cycle progression observed in HF cells suggests that the interaction and synergy between C͞EBP␣ and RAP is sufficient to up-regulate both the C͞EBP␣ and p21 proteins.…”

Regulation of cellular and viral protein expression by the Epstein-Barr virus transcriptional regulator Zta: Implications for therapy of EBV associated tumors

“…90 These data implied that Zta altered cell cycle progression through elevating levels of functional p53. It was also demonstrated that Zta-mediated G 0 /G 1 growth arrest was most readily observed in tumor cell lines expressing wild-type p53 and correlated with the posttranscriptional induction of p53.…”

Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

“…43 The 53BP1 itself can functionally regulate G2/M-phase DNA damage-activated cellcycle checkpoints after IR. 45,46 BZLF1 induces cell-cycle arrest in different cell lines, 47,48 and both G2 and mitotic block in HeLa cells. 49 As our study showed that BZLF1 could block the accumulation of 53BP1 and RNF8 proteins at the sites of DNA breaks, we further examined the effect of BZLF1 on IRinduced cell-cycle arrest.…”