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Role of NF-kappa B in TNF-alpha induced apoptosis The term apoptosis is derived from the Greek word that signifies the dropping of leaves from the trees. This term is applied to a group of characteristic structural and molecular events that separate this type of cell deletion from necrosis (Table I). In contrast to necrosis that involves a group of cells simultaneously, apoptosis may occur in a single cell surrounded by a group of viable cells. There is a distinct and precisely localized control over the fate of specific cells in a mixed cell population that undergo apoptosis. Apoptosis is a selective process for deletion of cells in various biological systems. This event similar to proliferation is tightly regulated (table II) with both processes playing essential roles in the homeostasis of renewable tissues. A diverse group of signals induce apoptosis (Table III). Based on sequence homology, a large family of molecules collectively called the nerve growth factor/TNF receptor family of apoptosis inducing signaling proteins has been identified (Table IV). In addition, the extracellular domains of the TNFr family bears significant homology to the open reading frames (ORFs) of several viruses. Over the past two years, ligands for most of the known receptors of the nerve growth factor/TNF receptor family have been identified. These ligands are all type II transmembrane proteins and show homology to TNF and lymphotoxin (LT) and therefore belong to a TNF family of molecules. TNF-alpha is one of the prime signals that induces apoptosis in a host of cells. TNF-alpha also activates the transcription factor NF-kappa B. It has not been clear whether the TNF-alpha induced apoptosis and activation of NF-kappa B are linked. In the November 1, 1996 issue of Science, three groups report that these effects of TNF-alpha are linked. NF-kappa B plays a protective role in the apoptosis induced by TNF-alpha (Wang et al. 1996, Antwerp et al, 1996, Beg and Baltimore, 1996). In addition, the activation of this transcription factor, plays a similar role in the apoptosis induced by ionizing radition and the chemotherapeutic agent, daunorubricin (Wang et al, 1996).
The most common forms of the NF-kappa B is a 50 kd heterodimer protein (p50) and a 65 kd protein which is also called RelA or p65. These investigators showed that the protective effect of the NF-kappa B is mediated by NF-kappa B subunits. Treatment of the RelA deficient mouse fibroblasts (Rel A -/-) and macrophages with TNF-alpha resulted in apoptosis of a significant number of cells whereas the RelA (+/+) cells were spared from this effect of TNF-alpha. Reintroduction of the RelA into the Rel A -/- promoted survival of the cells after treatment with TNF-alpha (Beg and Baltimore, 1996). Expression of p65 and p55 also confered protection against apoptosis induced by TNF-alpha (Wang et al, 1996). The apoptosis inducing effect of TNF-alpha was also enhanced by a proteasome inhibitor, MG132 (Z-Leu-Leu-Leu-H), that inhibits the NF-kappa B (Wang et al, 1996) and by dominant-negative I REFERENCES:
Wang C-Y, Mayo MW, Baldwin AS: TNF-
Antwerp DJV, Martin SJ, Kafri T, Green DR, Verma IM: Suprresion of TNF-
Beg AA, Baltimore D: An essential role of NF-
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M (Antwerp et al, 1996). On the other hand, the apoptosis induced by a combination of TNF-alpha and cyclohexamide was inhbited by IL-1 that is a strong activator of NF-kappa B (Wang et al, 1996). Taken together, the findings show that NF-kappa B protects against the apoptosis induced by TNF-alpha. This insight would be useful for devising strategies in the treatment of cancer and inflammatory responses that involve TNF-alpha.
