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

Abstract

Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic DNA virus that causes Kaposi sarcoma and AIDS-related primary effusion lymphoma (PEL). Here we show that KSHV lytic cycle replication in PEL cells induces G1 cell cycle arrest, presumably to facilitate the progression of viral DNA replication. Expression of a KSHV-encoded early lytic protein referred to as RAP or K8 is induced within 12-24 h after the onset of lytic cycle induction in host PEL cells, and coincides with increased levels of both the endogenous C͞EBP␣ and p21 CIP-1 proteins in the nucleus of the same cells. The KSHV RAP protein binds to C͞EBP␣ in vitro and stimulates C͞EBP␣-induced expression from both the C͞EBP␣ and p21 promoters in cotransfected cells. A recombinant adenovirus expressing the RAP protein induced the expression of both the C͞EBP␣ and p21 proteins in primary human fibroblasts, and flow cytometric analysis revealed a dramatic inhibition of G1 to S cell cycle progression in the same cells. All of these effects were abolished in cells that lack C͞EBP␣ or by deletion of the basic͞ leucine zipper region in RAP that interacts with C͞EBP␣. Therefore, C͞EBP␣ is essential for the p21-mediated inhibition of G1 to S-phase progression by RAP in KSHV-infected host cells.

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

“…It has been suggested that during the early stage of herpesvirus infection, cells are often blocked at G 1 stage to allow viral mRNA and proteins to be synthesized before the onset of cellular DNA replication. In previous studies, K-bZIP was shown to be a key cell cycle regulator that binds Cdk2 and activates p21 to slow down the cell cycle at the immediate-early stage of lytic infection (21,55). Accordingly, we suggest that, at the later stages of viral replication, vPK restores the Cdk2 function by phosphorylating Cdk2 targets, and vPK may compete with Cdk2, thereby releasing Cdk2 from its complex with K-bZIP.…”

bZIP proteins of human gammaherpesviruses

“…Importantly, neither Zta nor K-bZIP are able to effect a cell cycle arrest in C/EBPa knock-out fibroblasts and cell lines (Wu et al, 2002. As detailed above, both Zta and K-bZIP physically interact with C/EBPa and stimulate the ability of C/EBPa to transactivate dependent promoters (Wu et al, 2002.…”

“…This appears to activate the transcriptional function of C/EBPa, leading to enhanced expression of C/EBPa and a downstream target, p21 CIP1 , which is thought to effect cell cycle arrest (Wu et al, 2002. The ability to activate C/EBPa and p21 requires the C-terminal half of both Zta and K-bZIP (Wu et al, 2002.…”

“…Part of the mechanism behind the cell cycle effects involves C/EBPa (Wu et al, 2002Wang et al, 2003). Importantly, neither Zta nor K-bZIP are able to effect a cell cycle arrest in C/EBPa knock-out fibroblasts and cell lines (Wu et al, 2002.…”

A Nonclassic CCAAT Enhancer Element Binding Protein Binding Site Contributes to α-Methylacyl-CoA Racemase Expression in Prostate Cancer

“…C/EBPa expression is associated with increased expression of p21 cell cycle inhibitory protein (16), cell cycle arrest after viral infection (17), and terminal differentiation (18). Loss-of-function mutations in C/EBPa are pro-proliferative and have been reported in acute myeloblastic leukemia (19).…”