Biology Reference
In-Depth Information
cyclin B1 accumulates in infected cells due to stabilization of the protein, with only
minimal changes in RNA levels (Salvant et al. 1998; Sanchez et al. 2003). The
degradation of cyclin B1 is mediated by the anaphase-promoting complex (APC),
an E3 ubiquitin ligase. Interestingly, other substrates of the APC also accumulate
in infected cells, including securin, geminin, Aurora B, and cdc6 (Biswas et al.
2003; Wiebusch et al. 2005). The increase in the steady-state levels of these pro-
teins suggests that the APC is inactivated during infection. Data from our lab and
others suggest that this dysregulation is due to the dismantling of the APC early in
infection (Wiebusch et al. 2005; Tran et al. 2008).
Importance of Subversion of the Cell Cycle
for the Viral Infection
Cell Cycle Arrest
A surprising observation regarding the kinetics of HCMV replication was that the
initiation of the viral gene expression requires that the cells be in G
0
or G
1
at the
time of infection. When cells are infected near or during S phase, many cells are
able to pass through S phase and undergo mitosis prior to the synthesis of IE and
early gene products (Salvant et al. 1998; Fortunato et al. 2002). The process of cell
cycle arrest appears to be important for the early phase of infection, and proteins
carried in the virus particle as well as those expressed at immediate early times
contribute to this process (see Fig. 2).
Proteins in the Virus Particle
Two virion proteins, pUL69 and pp71 (pUL82), have been shown to modulate cell
cycle progression (see the chapter by R. Kalejta, this volume). As components of
the virion tegument, they can function as soon as the virus enters the cells. In the
case of pUL69, overexpression of this protein stimulates accumulation of cells in
G
1
phase of the cell cycle (Lu and Shenk 1999). In addition, cells infected with a
virus lacking functional pUL69 do not efficiently undergo cell cycle arrest (Hayashi
et al. 2000). This mutant does not replicate to wild type levels, but the growth defect
may be attributed to other functions of pUL69.
The deletion of pp71 also creates a virus that is severely impaired for growth.
The growth defect can be complemented by expression of the protein in trans
(Bresnahan and Shenk 2000; Dunn et al. 2003). pp71 has been shown to interact
with the cell growth suppressors Rb, p107, and p130 and to target hypophosphor-
ylated forms of these pocket proteins for degradation by the proteasome (Kalejta
et al. 2003). Consistent with this activity, pp71 expression in uninfected cells accel-
erates their progression through G1 phase, but does not change the overall doubling
