Shao R, Hu M C, Zhou B P, Lin S Y, Chiao P J, von Lindern R H, Spohn B, Hung M C
Section of Molecular Cell Biology, Department of Cancer Biology, Breast Cancer Basic Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Biol Chem. 1999 Jul 30;274(31):21495-8. doi: 10.1074/jbc.274.31.21495.
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 kappaB (NF-kappaB) has been shown to play an anti-apoptotic role in TNF-induced apoptosis, we examined apoptotic susceptibility and NF-kappaB activation induced by TNF in the E1A transfectants and their parental cells. Here, we reported that E1A inhibited activation of NF-kappaB and rendered cells more sensitive to TNF-induced apoptosis. We further showed that this inhibition was through suppression of IkappaB kinase (IKK) activity and IkappaB phosphorylation. Moreover, deletion of the p300 and Rb binding domains of E1A abolished its function in blocking IKK activity and IkappaB phosphorylation, suggesting that these domains are essential for the E1A function in down-regulating IKK activity and NF-kappaB 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.
腺病毒E1A蛋白与增加细胞对肿瘤坏死因子（TNF）诱导的凋亡的敏感性有关；然而，其作用机制仍不清楚。由于已证明核因子κB（NF-κB）的激活在TNF诱导的凋亡中起抗凋亡作用，我们检测了E1A转染细胞及其亲本细胞中TNF诱导的凋亡敏感性和NF-κB激活情况。在此，我们报道E1A抑制NF-κB的激活，并使细胞对TNF诱导的凋亡更敏感。我们进一步表明，这种抑制是通过抑制IκB激酶（IKK）活性和IκB磷酸化实现的。此外，E1A的p300和Rb结合结构域的缺失消除了其阻断IKK活性和IκB磷酸化的功能，表明这些结构域对于E1A下调IKK活性和NF-κB信号传导的功能至关重要。然而，E1A抑制IKK活性的作用可能是间接的。尽管如此，我们的结果表明，E1A抑制IKK活性是E1A介导的TNF诱导凋亡致敏作用的重要机制。
