Biology Reference
In-Depth Information
the pocket protein p107 (Margolis et al. 1995; Poma et al. 1996; Woo et al. 1997;
Castano et al. 1998; Hansen et al. 2001; Zhang et al. 2003). IE1-72 alleviates p107-
mediated repression of E2F-responsive promoters in transient transfection assays
and thus may stimulate S-phase entry. Additionally, IE1-72 can reverse the
inhibitory effects of p107 on cdk2/cyclin E kinase activity, which may also facili-
tate the G
1
/S transition. It has been proposed that the formation of an IE1-72/p107
complex mediates these effects (Poma et al. 1996; Johnson et al. 1999; Zhang et al.
2003); however, the finding that IE1-72 can phosphorylate p107, p130, and E2F
proteins (Pajovic et al. 1997) raises the possibility that some of the effects of IE1-72
on transcription and the cell cycle result from its reported kinase activity.
Immediate Early Protein 2
Several studies have shown that transient expression of IE2-86 alters cell cycle
progression, with a block at the G1/S boundary in a p53
+/+
cell or after entry into S
phase in a p53 mutant cell (Murphy et al. 2000; Wiebusch and Hagemeier 2001;
Noris et al. 2002; Wiebusch et al. 2003; Song and Stinski 2005) (see the chapter by
M.F. Stinski and D.T. Petrik, this volume). In transient transfection assays, deletion
of aa 451-579 abolished the ability of IE2-86 to induce G1 arrest in transient assays
in U373 cells (Wiebusch and Hagemeier 1999). Perhaps the most convincing evi-
dence that IE2-86 plays a role in cell cycle arrest is a recent study showing that a
mutation of aa 548 of IE2-86 from Q to R results in a growth-impaired virus that
does not inhibit cellular DNA synthesis or the cell cycle (Petrik et al. 2006). The
observation that this mutant IE2-86 could still autoregulate the MIE promoter and
activate viral early genes provides further evidence that efficient viral replication
also requires the inhibition of host cell DNA synthesis.
Early observations showing that IE2-86 interacts with several proteins regulat-
ing the cell cycle, including Rb and p53, made it reasonable to link some of its
functions to cell cycle arrest (Hagemeier et al. 1994; Sommer et al. 1994; Speir
et al. 1994; Bonin and McDougall 1997; Fortunato et al. 1997). p53 levels are
stabilized in infected cells but the expression of its target gene p21 is repressed
(Muganda et al. 1994; Bresnahan et al. 1996b; Fortunato and Spector 1998; Chen
et al. 2001). In transient expression and in vitro systems
,
IE2-86 interacts with the
C-terminus of p53, and the binding of p53 to target promoters is inhibited (Speir
et al. 1994; Bonin and McDougall 1997; Hsu et al. 2004). IE2-86 expression also
inhibits the acetylation of p53 and of histones in proximity to p53-dependent
promoters (Hsu et al. 2004), and thus IE2-86 may regulate expression of p53
target genes by multiple mechanisms. These effects on protein acetylation may
result from downregulation of p300/CBP histone acetyl transferase (HAT) activ-
ity, which was detected in a complex with p53 and IE2-86 (Hsu et al. 2004). It is
possible that the inhibition of p300/CBP HAT activity is p53-promoter-specific,
as IE2-86 did not suppress histone acetylation globally. The biological relevance
of these experiments must be considered with caution, given that none were per-
formed in the context of the viral infection.
