Biology Reference
In-Depth Information
E2F-responsive promoters, but fails to regulate cell cycle progression (Petrik
et al. 2006). The virus replicates slowly because viral DNA synthesis is in com-
petition with cellular DNA synthesis. Therefore, arrest of cell cycle progression
by the IE86 protein and prevention of cellular DNA synthesis are critical steps
for efficient HCMV replication.
The mutation of glutamine at residue 548 to arginine in the Q548R recombinant
virus is unique because the IE86 protein fails to regulate the cell cycle at both the
G1/S and G2/
phases (Petrik et al. 2006). In stable cell lines, the Q548R mutant
IE86 protein complexes with p53 and the cells continue to divide (Bonin and
McDougall 1997; Murphy et al. 2000). While the Q548R mutant IE86 protein
stimulates cellular E2F gene expression and unscheduled entry into the S phase, it
cannot transform cells. The mutant viral protein may not be able to overcome con-
tact inhibition or other cellular processes necessary for cellular transformation. It is
likely that the Q548R mutant IE86 protein fails to bind and degrade Mdm2, allowing
both cellular DNA synthesis and normal progression into G2/
Μ
. The introduction of
a positively charged arginine at residue 548 may inhibit IE86 protein interaction
with a cellular protein. In contrast, substitution of residue 548 with a neutral alanine
residue had little to no effect (Petrik et al. 2006). In addition, the Q548R mutant viral
protein may also fail to degrade the anaphase promoting complex/cyclosome (APC/C),
which is an E3 ubiquitin ligase that targets regulators of cell division for degradation
by the proteasome (Peters 2006). APC/C causes lower levels of cyclin B/cdk1, and
cyclin B degradation is necessary to release the cell cycle from G
2
/
Μ
back into G
1
(Peters 2006). HCMV infection inactivates APC/C and the IE86 protein may be the
cause of this inactivation (Wiebusch et al. 2005).
The UL69 gene product is also reported to arrest the cell cycle when overex-
pressed from a viral vector (Hayashi et al. 2000). Our results with the Q548R
recombinant virus indicate that the cell cycle is not arrested when UL69 is present.
These results may suggest that both UL69 and a functional IE86 protein are
required to efficiently arrest the cell cycle during viral infection. The IE86 protein
of HCMV is different from DNA tumor virus early regulatory proteins because it
also stops cycle progression at the G1/S interface in p53
+/+
cells or at G
2
/
Μ
in p53-
null cells. Nevertheless, apoptosis is prevented in the HCMV-infected cell by the
viral IE proteins expressed from the UL36, UL37X1, and UL38 genes (see the
chapter by A.L. McCormick, this volume). In addition, the IE86 protein itself is
reported to inhibit apoptosis under special circumstances (Zhu et al. 1995).
Μ
Perspectives
The IE86 protein of HCMV is an essential viral protein that does the following
during viral replication:
1. It negatively autoregulates the MIE enhancer-containing promoter, which con-
trols the expression of IE72 and IE86 proteins.
