Subversion of Cell Cycle Regulatory Pathways - Human Cytomegalovirus - page 240

coordinates multiple cellular processes through its activity as a transcriptional
activator and repressor in response to stress and growth factors (Vousden and Lu
2002; Slee et al. 2004). Phosphorylation of p53 controls its association with
MDM2, which targets p53 for degradation by the proteasome (for review see
Lavin and Gueven 2006). In response to DNA damage, nutrient deprivation, and
other insults to the cell, p53 levels are stabilized. This can lead to the expression
of the cdk inhibitor p21 as well as induction of several pro-apoptotic genes.
The Effect of HCMV on the Cell Cycle
Cell Cycle Arrest and cdk Dysregulation
Cells infected with HCMV in the G 0 /G 1 phase of the cycle do not replicate their
DNA and arrest in a pseudo-G 1 state that is distinguished by the expression of
selected G 1 -phase, S-phase and M-phase gene products (Jault et al. 1995;
Bresnahan et al. 1996b; Lu and Shenk 1996; Dittmer and Mocarski 1997; Salvant
et al. 1998; Wiebusch and Hagemeier 1999; Wiebusch and Hagemeier 2001;
Challacombe et al. 2004; Hertel and Mocarski 2004) (see Fig. 1). The G 1 /S- and
G 2 / M-phase cyclins E and B1, respectively, accumulate in infected cells with a
concomitant increase in associated kinase activity (Jault et al. 1995; Wiebusch
and Hagemeier 2001; Sanchez et al. 2003). In contrast, the steady-state levels of
the S-phase cyclin A and G 1 -phase cyclin D1 are reduced (Jault et al. 1995;
Bresnahan et al. 1996b; Salvant et al. 1998; Wiebusch and Hagemeier 2001). The
effects of the virus on cyclins E, A, and D1, are at the level of transcription, while
accumulation of cyclin B1 is associated with increased stability of the protein
(Salvant et al. 1998; Sanchez et al. 2003).
Checkpoint Control and DNA Damage
The observation that HCMV infection during S phase induces breaks in chromo-
some 1 has prompted investigations into the effects of infection on DNA damage
pathways (Fortunato et al. 2000). Infection of cells with HCMV causes signifi-
cant changes in proteins involved in G 1 and S phase checkpoint control. For
example, the tumor suppressors Rb, p130, and p107, which inhibit the expression
of E2F-responsive genes and the activity of cdk2 kinase complexes, are main-
tained in an inactivate phosphorylated state in infected cells (Jault et al. 1995;
McElroy et al. 2000). Interestingly, it has also been reported that HCMV-infected
cells express high levels of the p16 Ink4 tumor suppressor (Noris et al. 2002;
Zannetti et al. 2006). p16 Ink4 is a marker for senescence and activator of Rb
through binding and inactivation of Cdk4 and Cdk6 kinases.