E1A sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of IκB kinases and nuclear factor κB activities

The adenovirus E1A protein has been implicated in increasing cellular susceptibility to apoptosis induced by tumor necrosis factor (TNF); however, its mechanism of action is still unknown. Since activation of nuclear factor κB (NF-κB) has been shown to play an anti-apoptotic role in TNF-induced apoptosis, we examined apoptotic susceptibility and NF-κB activation induced by TNF in the E1A transfectants and their parental cells. Here, we reported that E1A inhibited activation of NF-κB and rendered cells more sensitive to TNF-induced apoptosis. We further showed that this inhibition was through suppression of IκB kinase (IKK) activity and IκB phosphorylation. Moreover, deletion of the p300 and Rb binding domains of E1A abolished its function in blocking IKK activity and IκB phosphorylation, suggesting that these domains are essential for the E1A function in down-regulating IKK activity and NF-κB signaling. However, the role of E1A in inhibiting IKK activity might be indirect. Nevertheless, our results suggest that inhibition of IKK activity by E1A is an important mechanism for the E1A-mediated sensitization of TNF- induced apoptosis.