Rp. Shao et al., E1A sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of I kappa B kinases and nuclear factor kappa B activities, J BIOL CHEM, 274(31), 1999, pp. 21495-21498
The adenovirus E1A protein has been implicated in increasing cellular susce
ptibility to apoptosis induced by tumor necrosis factor (TNF); however, its
mechanism of action is still unknown. Since activation of nuclear factor k
appa B (NF-kappa B) has been shown to play an anti-apoptotic role in TNF-in
duced apoptosis, we examined apoptotic susceptibility and NF-kappa B activa
tion induced by TNF in the E1A transfectants and their parental cells. Here
, we reported that E1A inhibited activation of NF-kappa B and rendered cell
s more sensitive to TNF-induced apoptosis. We further showed that this inhi
bition was through suppression of I kappa B kinase (IKK) activity and I kap
pa B phosphorylation. Moreover, deletion of the p300 and Rb binding domains
of E1A abolished its function in blocking IKK activity and I kappa B phosp
horylation, suggesting that these domains are essential for the E1A functio
n in down-regulating IKK activity and NF-kappa B signaling. However, the ro
le of E1A in inhibiting IKK activity might be indirect. Nevertheless, our r
esults suggest that inhibition of IKK activity by E1A is an important mecha
nism for the E1A-mediated sensitization of TNF-induced apoptosis.