Adenovirus E1A sensitizes cells to the cytotoxic action of tumor necrosis factor α (TNF-α). This effect has been attributed to direct blockade of NF-κB activation, as well as to increased activation of components of the apoptotic pathway and decreases in inhibitors of apoptosis. In this report we evaluated the mechanism by which E1A modulates the expression of the cytokine-inducible cytoprotective genes manganese superoxide dismutase (MnSOD), interleukin-6 (IL-6), and ferritin heavy chain (FH). We observed that E1A blocks induction of MnSOD, IL-6, and FH by TNF-α or IL-1α. Because NF-κB plays a role in cytokine-dependent induction of MnSOD, IL-6, and FH, we assessed the effect of E1A on NF-κB in cells treated with TNF. IκB, the inhibitor of NF-κB, was degraded similarly in the presence and absence of E1A. TNF induced a quantitatively and temporally equivalent activation of NF-κB in control and E1A-transfected cells. However, TNF-dependent acetylation of NF-κB was diminished in cells expressing E1A. E1A mutants unable to bind p400 or the Rb family proteins were still capable of repressing TNF-dependent induction of FH. However, mutants of E1A that abrogated binding of p300/CBP blocked the ability of E1A to repress TNF-dependent induction of FH. These results suggest that p300/ CBP is a critical control point in NF-κB-dependent transcriptional regulation of cytoprotective genes by cytokines.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology