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J. Virol., May 1997, 3515-3525, Vol 71, No. 5
SK Chiou and E White
E1A expression during adenovirus infection induces apoptosis. E1A
expression causes accumulation of the p53 tumor suppressor protein, and
E1A-induced apoptosis is p53 mediated in primary rodent cells, implying
that p53 induction may be linked to apoptosis induction by E1A.
Adenoviruses containing mutations in the E1A gene were tested for the
ability to trigger both p53 accumulation and the appearance of enhanced
cytopathy (cyt phenotype) and degradation of DNA (deg phenotype),
indicative of apoptosis in infected HeLa cells. The adenoviruses had
mutations which disrupted the pRb- and/or p300-binding activities of E1A so
that the relationship between p53 induction and apoptosis and binding to
these cellular proteins by E1A could be determined. An E1A mutation that
specifically disrupted the p300-binding activity failed to induce p53
accumulation, whereas mutations in E1A which affected pRb binding induced
p53 accumulation. Thus, p300 binding was required and pRb binding was
dispensable for E1A-mediated accumulation of p53 in HeLa cells. All the E1A
mutant viruses, regardless of the ability to induce p53 accumulation,
induced the cyt and deg phenotypes, suggesting that p53 induction in
infected HeLa cells was not essential for apoptosis, nor was binding of E1A
to the pRb and/or p300 protein. The possibility that E1A induced a
p53-independent apoptosis pathway was tested by analyzing the appearance of
the cyt and deg phenotypes in Saos-2 cells, which were null for both
alleles of p53, upon adenovirus infection. An adenovirus expressing
wild-type 12S E1A induced both the cyt and deg phenotypes in Saos-2 cells,
as did all the E1A mutant viruses. Thus, E1A expression during infection of
human cells may trigger redundant p53-independent and -dependent apoptotic
pathways.
Copyright © 1997, American Society for Microbiology
p300 binding by E1A cosegregates with p53 induction but is dispensable for apoptosis
Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA.
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