The Dual Effect of Adenovirus Type 5 E1A 13S Protein on NF-κB Activation Is Antagonized by E1B 19K

Abstract

The genomes of human adenoviruses encode several regulatory proteins, including the two differentially spliced gene products E1A and E1B. Here, we show that the 13S but not the 12S splice variant of E1A of adenovirus type 5 can activate the human transcription factor NF-B in a bimodal fashion. One mode is the activation of NF-B containing the p65 subunit from the cytoplasmic NF-B-IB complex. This activation required reactive oxygen intermediates and the phosphorylation of IB␣ at serines 32 and 36, followed by IB␣ degradation and the nuclear uptake of NF-B. In addition, 13S E1A stimulated the transcriptional activity of the C-terminal 80 amino acids of p65 at a core promoter with either a TATA box or an initiator (INR) element. The C-terminal 80 amino acids of p65 were found to associate with E1A in vitro. The activation of NF-Bdependent reporter gene transcription by E1A was potently suppressed upon coexpression of the E1B 19-kDa protein (19K). E1B 19K prevented both the activation of NF-B and the E1A-mediated transcriptional enhancement of p65. These inhibitory effects were not found for the 55-kDa splice variant of the E1B protein.We suggest that the inductive effect of E1A 13S on the host factor NF-B, whose activation is important for the transcription of various adenovirus genes, must be counteracted by the suppressive effect of E1B 19K so that the adenovirus-infected cell can escape the immune-stimulatory and apoptotic effects of NF-B.

INK4 cell cycle inhibitors direct transcriptional inactivation of NF-κB

“…The position of proteins are indicated kBp65 and block its transactivation activity. In contrast to INK4 molecules, the basic transcription factors TFIIB and TATA-binding protein (TBP), the coactivators p300 and CBP as well as the viral encoded factor E1A 13S stimulate NF-kBp65-dependent transcription (Schmitz et al, 1996;Gerritsen et al, 1997;Paal et al, 1997;Perkins et al, 1997). These molecules directly associate with the C-terminal transactivation domain of NF-kBp65 corresponding to our observation that INK4 proteins interact with NF-kBp65, but do not interact with NF-kBp50 (Figure 2).…”

Transcriptional and post-transcriptional regulation of κB-controlled genes by pp60v-src

“…This activation of NF-kB is generally dependent on increased turnover of IkB-a and/or IkB-b. In addition, virally infected cells with increased NF-kB activity express elevated levels of the NF-kB1 and IkB-a mRNAs (Arima et al, 1991; Kowalik et al, 1993; Lacoste et al, 1995;Herrero et al, 1995;Good and Sun, 1996;Schmitz et al, 1996). While we did not examine the level of IkB-b or IkB-e in RSVtransformed CEF, no major change in the expression of NF-kB1 or IkB-a was observed in these cells ( Figure 5 and data not shown).…”

Distinct Domains of the RelA NF-κB Subunit Are Required for Negative Cross-talk and Direct Interaction with the Glucocorticoid Receptor

“…An important difference between COS-1 cells and 293 cells is that 293 cells contain E1A protein (28). Furthermore, it has previously been described that 13 S E1A was able to associate with the C-terminal part of RelA and to stimulate the transcriptional activity of RelA (29). Therefore, we investigated the possible role of E1A in the transrepression potential of RelA.…”