Role of Human Cytomegalovirus Immediate-Early Proteins in Cell Growth Control

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been implicated in several disorders, including an association between HCMV reactivation and the overproliferation of arterial smooth muscle cells observed in restenosis. Although HCMV can mediate a growth-arrest phenotype in infected cells, the virus can also promote an environment conducive to proliferation. Here, we present evidence that the HCMV immediateearly (IE) proteins, IE1-72 and IE2-86, may be responsible for inducing this proliferative environment by altering cell cycle control. We find that expression of either of these IE proteins can alter the cell cycle distribution of randomly cycling cells towards S and G 2 /M phases. Additionally, we find that expression of IE2-86, but not IE1-72, induces quiescent cells into S phase and delays cell cycle exit. In the absence of p53, IE1-72 expression can induce S phase and delay cell cycle exit. We also demonstrate that p53 protein levels increase in fibroblasts following the expression of IE1-72. The observed accumulation of p53 protein in IE1-72-expressing cells may account for the inability of IE1-72 to induce S phase and delay cell cycle exit. Our data suggest that expression of HCMV IE1-72 and IE2-86 is sufficient to alter the cell cycle to generate an environment conducive to proliferation.

Effect of the human cytomegalovirus IE86 protein on expression of E2F-responsive genes: A DNA microarray analysis

“…The up-regulation of E2F-responsive genes indicates cell cycle progression from G 0 ͞G 1 to S phase. Because the viral IE86 protein alone induces cell cycle progression into S phase and cellular DNA synthesis (11,(29)(30)(31) and transactivates the expression of cellular as well as viral genes (14-17, 22, 24), we assayed the effect of the IE86 protein on global cellular gene expression. HFF cells were transduced with recombinant adenovirus vectors expressing either the IE86 protein or GFP, and cytoplasmic RNAs were assayed by DNA microarray.…”

“…The IE86 protein alone pushes quiescent, serum-starved cells into S phase, but mutant IE86 protein does not (11,29,30). In IE86 protein expressing cells, cell division does not occur (11,30,31).…”

Compensation of BRG-1 Function by Brm

“…The green fluorescent protein (GFP) adenovirus was provided by Dr. Gustavo Leone (Ohio State University), and the p16ink4a adenovirus was supplied by Dr. Timothy Kowalik (University of Massachusetts) and prepared as previously described (43). The infections were performed at a calculated multiplicity of infection of 50 -100 for ϳ95-100% infection efficiency after 16 h, as judged by GFP expression.…”

“…Because BRG-1 is required for RB to mediate cell cycle arrest in response to p16ink4a, we examined whether this RB signaling pathway is intact in the disparate BRG-1 mutant tumor lines (17). Each indicated BRG-1 mutant line was infected with adenovirus encoding either GFP or p16ink4a and subsequently monitored for their ability to incorporate BrdUrd (43). As shown in Fig.…”

Cytoplasmic Translocation of p53 by Human Cytomegalovirus Infection

“…They all contribute in the transformation of the virusinfected cells. It was also reported that human cytomegalovirus (HCMV), one of large DNA viruses, induced the accumulation of p53 in the infected cells and altered cellular regulation and functions (10,11). HCMV has been related to cell cycle disturbance in some diseases.…”