Abstract
The early transcribed adenovirus proteins E1A and E1B display a variety of functions in the transformation of primary rodent cells and the regulation of apoptosis and transcription. We have recently shown recently that the E1B 19 kDa protein from Adenovirus 5 (Ad 5) can functionally antagonize the stimulatory effect of E1A 13S on the human transcription factor NF-kappaB. Here we show that expression of E1B 19 kDa negatively interfered with the activation of NF-kappaB by different stimuli, such as the E1A 13S protein, and treatment with phorbol ester and tumor necrosis factor alpha. This suggests that E1B 19 kDa acts on a common upstream signaling event. Band shift experiments showed that expression of E1B 19 kDa impaired the generation of the nuclear, DNA-binding form of NF-kappaB. Domain mapping experiments employing various E1B 19 kDa mutants revealed the necessity of a hydrophobic Bcl-2 homology region between amino acids 90 and 96 for NF-kappaB inhibition. Co-transfection experiments showed that the inhibitory effect of E1B 19 kDa on E1A 13S-activated NF-kappaB transcription was gradually lost in the course of time. Thus the continuous stimulatory action of E1A 13S can finally override the antagonistic effects of E1B 19 kDa on NF-kappaB activity. In contrast to E1B 19 kDa, expression of the E1B 55 kDa protein did not result in a de novo activation of NF-kappaB, but co-stimulated the transcriptional potential of activated NF-kappaB.
Highlights
E1B display a variety of functions in the transformation 289 (13S) amino acids length which have transforming activity
We have recently shown recently that the E1B 19 kDa protein from Adenovirus 5 (Ad 5) can functionally antagonize the stimulatory effect of E1A 13S on the human transcription factor NF-B
Both splice variants of E1B were found to strongly cooperate with E1A in cell transformation. This supportive effect of E1B in transformation is most likely due to its antiapoptotic properties (Rao et al, 1992). This idea is reinforced by the finding that adenoviruses defective in E1B can be functionally complemented by the cellular Bcl-2 gene, which acts as an inhibitor of apoptosis (Tarodi et al, 1993; Chiou et al, 1994)
Summary
E1B display a variety of functions in the transformation 289 (13S) amino acids length which have transforming activity. The absence of the E1B 19 kDa during the productive infection of human cells induces the degradation of host and viral DNA as well as an enhanced cytopathic effect (Ezoe et al, 1981; Pilder et al, 1984; Subramanian et al, 1984a, 1984b; White et al, 1984a, 1984b) Both splice variants of E1B were found to strongly cooperate with E1A in cell transformation. Bcl-2 proteins in the inhibition of apoptosis, both proteins are membrane-anchored, contain three short regions with sequence similarity, and interact with a common set of cellular proteins (Boyd et al, 1994) Both splice variants of E1B inhibit cell death induced by different apoptotic stimuli, such as E1A, the anti-cancer drug cisplatin, TNF-␣, or Fas antigen, the E1B 19 kDa protein does so more effectively (Gooding et al, 1991; Hashimoto et al, 1991; Debbas and White, 1993; Subramanian et al, 1993).
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