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J. Cell Biol.,
Volume 140, Number 3, February 9, 1998 637-645
Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6
In the absence of E1B, the 289-amino acid
product of human adenovirus type 5 13S E1A induces
p53-independent apoptosis by a mechanism that requires viral E4 gene products (Marcellus, R.C., J.C.
Teodoro, T. Wu, D.E. Brough, G. Ketner, G.C. Shore,
and P.E. Branton. 1996. J. Virol. 70:6207-6215) and involves a mechanism that includes activation of caspases
(Boulakia, C.A., G. Chen, F.W. Ng, J.G. Teodoro, P.E.
Branton, D.W. Nicholson, G.G. Poirier, and G.C.
Shore. 1996. Oncogene. 12:529-535). Here, we show
that one of the E4 products, E4orf4, is highly toxic
upon expression in rodent cells regardless of the p53
status, and that this cytotoxicity is significantly overcome by coexpression with either Bcl-2 or Bcl-XL. Conditional expression of E4orf4 induces a cell death process that is characterized by apoptotic hallmark
features, such as externalization of phosphatidylserine,
loss of mitochondrial membrane potential, cytoplasmic
vacuolation, condensation of chromatin, and internucleosomal DNA degradation. However, the wide-spectrum inhibitor of caspases, tetrapeptide zVAD-fmk,
does not affect any of these apoptogenic manifestations, and does not alter the kinetics of E4orf4-induced
cell death. Moreover, E4orf4 expression does not result
in activation of the downstream effector caspase common to most apoptosis-inducing events, caspase-3
(CPP32). We conclude, therefore, that in the absence of
E1A, E4orf4 is sufficient by itself to trigger a p53-independent apoptosis pathway that may operate independently of the known zVAD-inhibitable caspases, and
that may involve an as yet uncharacterized mechanism.
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