The 19-Kilodalton Adenovirus E1B Transforming Protein Inhibits Programmed Cell Death and Prevents Cytolysis by Tumor Necrosis Factor α

Abstract

The adenovirus E1A and E1B proteins are required for transformation of primary rodent cells. When expressed in the absence of the 19,000-dalton (19K) E1B protein, however, the E1A proteins are acutely cytotoxic and induce host cell chromosomal DNA fragmentation and cytolysis, analogous to cells undergoing programmed cell death (apoptosis). E1A alone can efficiently initiate the formation of foci which subsequently undergo abortive transformation whereby stimulation of cell growth is counteracted by continual cell death. Cell lines with an immortalized growth potential eventually arise with low frequency. Coexpression of the E1B 19K protein with E1A is sufficient to overcome abortive transformation to produce high-frequency transformation. Like E1A, the tumoricidal cytokine tumor necrosis factor alpha (TNF-alpha) evokes a programmed cell death response in many tumor cell lines by inducing DNA fragmentation and cytolysis. Expression of the E1B 19K protein by viral infection, by transient expression, or in transformed cells completely and specifically blocks this TNF-alpha-induced DNA fragmentation and cell death. Cosegregation of 19K protein transforming activity with protection from TNF-alpha-mediated cytolysis demonstrates that both activities are likely the consequence of the same function of the protein. Therefore, we propose that by suppressing an intrinsic cell death mechanism activated by TNF-alpha or E1A, the E1B 19K protein enhances the transforming activity of E1A and enables adenovirus to evade TNF-alpha-dependent immune surveillance.

Bim: a novel member of the Bcl-2 family that promotes apoptosis

“…Bcl‐2 itself was the first intracellular regulator of apoptosis to be identified (Vaux et al ., 1988), and high levels enhance cell survival under diverse cytotoxic conditions (Sentman et al ., 1991; Strasser et al ., 1991). Other cellular homologues, such as Bcl‐x L (Boise et al ., 1993) and Bcl‐w (Gibson et al ., 1996), also enhance cell survival, as do more distantly related viral homologues, such as the adenovirus E1B19K protein (White et al ., 1992) and Epstein–Barr virus (EBV) BHRF‐1 (Henderson et al ., 1993). Remarkably, the family also includes members such as Bax (Oltvai et al ., 1993) and Bak (Chittenden et al ., 1995b; Farrow et al ., 1995; Kiefer et al ., 1995) which antagonize the activity of the pro‐survival proteins and provoke apoptosis when expressed at high concentrations.…”

HECTD1 is both a positive regulator and substrate of caspase-3 activity during apoptotic cell death

“…We next examined whether HECTD1 cleavage also occurred following activation of the extrinsic branches of apoptotic cell death using TNF-α/CHX co-stimulation (62). This was indeed the case, and we observed a banding pattern indicative of a single cleavage event of HECTD1 similar to the banding pattern observed following STS treatment ( Figure 1F ).…”

The Role of Chloride Channels in the Multidrug Resistance

“…Moreover, the nonstilbene derivative floretin, a VSOR blocker, inhibits cisplatin-induced caspase-3 activation in KB cells, thereby inhibiting apoptosis [59]. In human HeLa epithelial cells, human lymphoid U937 and murine neuroblastoma × rat glioma NG108-15 and rat PC12 pheochromocytoma, apoptosis was initiated by the use of staurosporine (STS) a known mitochondrial apoptosis inducer or inducer-mediated inducer of apoptosis, tumor necrosis factor α plus cycloheximide (TNF/CHX) [15,64,65]. Early-phase cell contraction associated with apoptosis, termed AVD, and all apoptotic events were completely inhibited by the C1 channel blocker, 5-nitro-2-(3-phenylpropylamino) benzoate (NPPB) or DIDS, SITS, niflumic acid, and glibenclamide49, which are known blockers of volume-sensitive Cl − channels61.…”