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© The Rockefeller University Press, 0021-9525/1998//637 $5.00
The Journal of Cell Biology, Volume 140, Number 3, , 1998 637-645

Article

E4orf4, a Novel Adenovirus Death Factor That Induces p53-independent Apoptosis by a Pathway That Is Not Inhibited by zVAD-fmk



Josée N. Lavoie, M. Nguyen, R.C. Marcellus, P.E. Branton, and G.C. Shore

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.

Abbreviations used in this paper: CPP32, caspase-3; DAPI, 4',6-diamidino-Z-phenylindole; HA, hemagglutinin; ICE, interleukin-1β–convertase enzyme; PARP, poly(ADP-ribosyl) polymerase; PP, protein phosphatase; rtTA, reverse tetracycline; TMRE, tetramethylrhodamine ethyl ester perchlorate.

This work was financed by operating grants from the National Cancer Institute of Canada (grant number 007307) and the Medical Research Council of Canada (grant number MT6192). J.N. Lavoie is supported by a Centennial Postdoctoral Fellowship from the Medical Research Council of Canada.

Address all correspondence to J.N. Lavoie, Department of Biochemistry, McGill University, 3655 Drummond St., Montreal, Quebec, Canada H3Y 1Y6. Tel.: (514) 398-8168. Fax: (514) 398-7384. E-mail: lavoie{at}medcor.mcgill.ca

2. Marcellus, R.C., J.N. Lavoie, D. Boivin, G.C. Shore, and P.E. Branton, manuscript in preparation.


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