Biology Reference
In-Depth Information
responsive promoters. Cyclin E/cdk1 expression and activity are increased by
HCMV or by the IE86 protein, which causes a feed-forward loop allowing ampli-
fication of signals that promote cell cycle progression from the G1 to S phase
(Jault et al. 1995; Salvant et al. 1998; McElroy et al. 2000; Sinclair et al. 2000). In
a normal cell, p53 induces cell cycle arrest, possibly to allow for DNA repair
(Kastan et al. 1992; Kuerbitz et al. 1992) or apoptosis to eliminate cells with dam-
aged genomes (Kuerbitz et al. 1992; Levine 1997; Prives and Hall 1999; Vogelstein
et al. 2000). In a p53
+/+
cell infected with a high multiplicity of HCMV, most of
the cells are blocked at G
1
/S (Jault et al. 1995; Bresnahan et al. 1996; Lu and
Shenk 1996; Morin et al. 1996; Dittmer and Mocarski 1997; Wiebusch and
Hagemeier 1999; Casavant et al. 2006). In a p53 mutant cell infected with HCMV,
viral replication is delayed and infectious virus production is decreased compared
to p53
+/+
cells (Murphy et al. 2000; Casavant et al. 2006). Wild type p53 expressed
in
trans
restores replication efficiency. Although p53 is not an essential cellular
protein for HCMV replication, a functional p53 contributes significantly to the
progression of infection.
In a p53
+/+
cell, the IE86 protein binds to p53 and the level of p53 increases in
the nucleus (Speir et al. 1994; Bonin and McDougall 1997; Fortunato and Spector
1998). p53 is stabilized by the IE86 protein in an atazia telangiectasis mutated
(ATM) kinase-positive cell but not in a ATM kinase-negative cell (Song and
Stinski 2004). ATM kinase phosphorylates p53 at serine residue 15, which stabi-
lizes the cellular protein by preventing Mdm2 ubiquitination (Song and Stinski
2004). Mdm2 is a p53-specific E3 ubiquitin ligase that promotes the degradation
of p53 (Haupt et al. 1997; Honda et al. 1997; Fang et al. 2000). Mdm2 forms an
autoregulatory feedback loop with p53 and allows p53 to control its own level and
activity by inducing the expression of Mdm2 (Fang et al. 2000). The IE86 protein
interrupts this cellular regulatory control by binding to Mdm2 and facilitating its
degradation (Zhang et al. 2006). Therefore, the IE86 protein decreases the level
of Mdm2, which increases the level of p53 in the HCMV-infected cell. In addi-
tion, phosphorylation at serine residues 15 and 20 of p53 hampers the Mdm2-p53
interaction, which prevents ubiquitination and degradation (Shieh et al. 1997;
Dumaz et al. 2001; Louria-Hayon et al. 2003).
There is also a correlation between high levels of IE86 and increased levels
of p21 (Shen et al. 2004; Song and Stinski 2004). The early increase in p53 and
p21 in the HCMV-infected cell may be related to an early intrinsic cellular
defense to virus replication (Garcia et al. 1997). Both IE72 and IE86 induce p21
in a p53-dependent manner (Song and Stinski 2004; Castillo et al. 2005). The
p21 promoter is activated by p53, but how IE72 or IE86 proteins increase p21 is
currently not understood. The IE86/p53 complex can still bind to the p53 cognate
site on DNA (Tsai et al. 1996), but it is uncertain whether IE86 or p53 activates
the p21 promoter. Alternatively, p21 could be activated prior to sequestration
of p53 in the nucleus with IE86. p21 can inhibit cdk2 and block the activity of
cyclin E, arresting the cell cycle progression, but this does not occur in the
HCMV-infected cell. It has been reported that IE86 can bind p21 and thereby
prevent p21 repression of cyclinE-dependent kinase activity (Sinclair et al.
2000). However, the cyclin E/cdk2 levels increase in both the HCMV-infected
