Cytomegalovirus infection induces high levels of cyclins, phosphorylated Rb, and p53, leading to cell cycle arrest

Abstract

Human cytomegalovirus (HCMV) infection stimulates cellular DNA synthesis and causes chromosomal damage. Because such events likely affect cellular proliferation, we investigated the impact of HCMV infection on key components of the cell cycle. Early after infection, HCMV induced elevated levels of cyclin E, cyclin E-associated kinase activity, and two tumor suppressor proteins, p53 and the retinoblastoma gene product (Rb). The steady-state concentration of Rb continued to rise throughout the infection, with most of the protein remaining in the highly phosphorylated form. At early times, HCMV infection also induced cyclin B accumulation, which was associated with a significant increase in mitosis-promoting factor activity as the infection progressed. In contrast, the levels of cyclin A and cyclin A-associated kinase activity increased only at late times in the infection, and the kinetics were delayed relative to those for cyclins E and B. Analysis of the cellular DNA content in the infected cells by flow cytometry showed a progressive shift of the cells from the G 1 to the S and G 2 /M phases of the cell cycle, leading to an accumulation of aneuploid cells at late times. We propose that these HCMV-mediated perturbations result in cell cycle arrest in G 2 /M.

Cell cycle perturbations induced by human herpesvirus 6 infection and their effect on virus replication

“…In our study, changes in cyclin D1 expression were not detected after infection, suggesting that the majority of the infected cells do not return to G1 phase after infection, as would be expected with normal cycling and division. In support of our findings, Jault et al [11] reported HCMV-induced G2/M arrest in cycling cells and found that high levels of cyclin E were induced, with cyclin A appearing only at late time points. De Bolle and coworkers [5] also reported that cyclin B1, cyclin A, and to a slight extent, cyclin E accumulated after HHV-6A infection in cord blood mononuclear cells.…”

Human herpesvirus 6 infection arrests cord blood mononuclear cells in G2 phase of the cell cycle

“…in the HHV-6A-infected condition, but this e¡ect was not maintained at later time points. These ¢ndings contrast with the HCMV-induced G 2 /M arrest in cycling cells, where induction of high levels of cyclin E was reported and cyclin A appeared only at late time points [19].…”

Human cytomegalovirus-inhibitory flavonoids: Studies on antiviral activity and mechanism of action

“…HCMV-infected fibroblasts were elsewhere shown to undergo cell cycle arrest (Jault et al, 1995;Dittmer and Mocarski, 1997). This was evidenced by increased levels of cyclin-dependent kinase 2 (cdk2), cyclin E, and proliferating cell nuclear antigen (PCNA), as well as cellular DNA levels consistent with a block at either G 1 /S or G 2 /M (Jault et al, 1995;Dittmer and Mocarski, 1997). Cell cycle arrest was reproduced in cells transfected with IE2-86 (Wiebusch and Hagemeier, 1999).…”