Adenovirus type 5 early region 4 is responsible for E1A-induced p53-independent apoptosis.
In the absence of E1B, the 289- and 243-residue E1A products of human adenovirus type 5 induce p53-dependent apoptosis. However, our group has shown recently that the 289-residue E1A protein is also able to induce apoptosis by a p53-independent mechanism (J. G. Teodoro, G. C. Shore, and P. E. Branton, Oncogene 11:467-474, 1995). Preliminary results suggested that p53-independent cell death required expression of one or more additional adenovirus early gene products. Here we show that both the E1B 19-kDa protein and cellular Bcl-2 inhibit or significantly delay p53-independent apoptosis. Neither early region E2 or E3 appeared to be necessary for such cell death. Analysis of a series of E1A mutants indicated that mutations in the transactivation domain and other regions of E1A correlated with E1A-mediated transactivation of E4 gene expression. Furthermore, p53-deficient human SAOS-2 cells infected with a mutant which expresses E1B but none of the E4 gene products remained viable for considerably longer times than those infected with wild-type adenovirus type 5. In addition, an adenovirus vector lacking both E1 and E4 was unable to induce DNA degradation and cell killing in E1A-expressing cell lines. These data showed that an E4 product is essential for E1A-induced p53-independent apoptosis.
Marcellus
R C
RC
Department of Biochemistry McGill University, Montréal, Quebec, Canada.
Teodoro
J G
JG
Wu
T
T
Brough
D E
DE
Ketner
G
G
Shore
G C
GC
Branton
P E
PE
D016475:3T3 Cells; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D004622:Embryo, Mammalian; D005347:Fibroblasts; D016158:Genes, p53; D006801:Humans; D007700:Kinetics; D051379:Mice; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D013997:Time Factors; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D017500:Adenovirus E1A Proteins; D016159:Tumor Suppressor Protein p53