Biology Reference
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Meier 2007; White and Spector 2007). Each has been connected to the PI3K/Akt
pro-survival pathway through the following. Initially, antiapoptotic roles for
IE1 491aa and IE2 579aa were suggested from results of transient and stable expression
in HeLa cells (Zhu et al. 1995). Here, either protein protects from short exposure
(8 h) to TNF or infection by E1B-19-kDa-deficient adenovirus, but not from UV
irradiation. Mechanisms are suggested to differ because antiapoptotic activity
maps to unique sequences. In comparison with vMIA, neither IE1 491aa nor IE2 579aa
protect HeLa cells undergoing TNF- or Fas-mediated apoptosis when evaluated in
a more rigorous assay (24 h) (Goldmacher et al. 1999). Thus, these proteins present
challenges for mechanistic studies.
One experimental approach that has suggested the mechanism of IE1 491aa and
IE2 579aa antiapoptotic function employed the temperature-sensitive ( ts ) BHK-21
cell line ts 13 (Lukac et al. 1997; Lukac and Alwine 1999; Yu and Alwine 2002).
At the nonpermissive temperature, a mutation in TAF II 250 produces transcription
alterations in specific genes that results in a block to cell cycle progression and the
induction of apoptosis in these hamster cells (Talavera and Basilico 1977; Sekiguchi
et al. 1988, 1995). When expressed from a genomic construct, IE1 491aa and IE2 579aa
prevent apoptosis and rescue promoter-specific transcription through independent
mechanisms that do not rescue cell cycle defects (Lukac et al. 1997; Lukac and
Alwine 1999). Further, IE rescue of transcription is primarily due to IE2 579aa (Lukac
et al. 1997), while either IE protein rescues apoptosis (Yu and Alwine 2002). Protein
domains required for protective function remain unidentified. Although the protec-
tive mechanism in this setting relies on PI3K activation of Akt, how IE1 491aa and
IE2 579aa promote this activation is unknown, as is the significance of these results to
infection. Nevertheless, these studies suggest hypotheses that may elucidate IE1 491aa
and IE2 579aa contributions to survival of infected cells.
UL38 Decreases Intrinsic Stress
The UL38 ORF maps to an intron of the UL37 gene (Tenney and Colberg-Poley
1990, 1991a, 1991b) (Fig. 1). The UL38 sequence is included on the unspliced
vMIA transcript and on a unique transcript with early kinetics. During infection,
pUL38 initially localizes to the nucleus but is well distributed between the nucleus
and cytoplasm by 24 h (Terhune et al. 2007). Mutagenesis of the UL38 ORF in
either Towne-BAC (Dunn et al. 2003) or pAD/Cre (Yu et al. 2002; Terhune et al.
2007) reduces yield by approximately 100-fold during a single round of replication
(Terhune et al. 2007).
The premature death induced by the UL38-null mutant virus and rescue by
addition of the pan-caspase inhibitor zVAD-fmk prompted further analysis of
pUL38 as an antiapoptotic factor (Terhune et al. 2007). Replication of the UL38
deletion mutant is also largely restored by zVAD-fmk. Death initiates very early
(24 h) and reaches more than 50% by 72 h, suggesting pUL38 is required very
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