[Frontiers in Bioscience 2, d49-60, February 15, 1997]

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Javier Gómez, David García-Domingo, Carlos Martínez-A.1 and Angelita Rebollo

Department of Immunology and Oncology, Centro Nacional de Biotecnología, Campus de Cantoblanco, E-28049 Madrid, Spain

Received 1/21/97; Accepted 1/30/97; On-line 2/15/97

5. NF-kappaB and apoptosis

Although past evidence linked the NF-kappaB family of transcription factors to the control of apoptotic responses, these relationships have been addressed only recently. Initial studies assigned c-Rel a role in apoptosis induction, since elevated subunit expression levels of these molecules were associated with programmed cell death both in the developing avian embryo and in bone marrow cells in vitro (82). Tetracycline-dependent induction of c-Rel expression in stably transfected HeLa cells causes the onset of apoptosis (31, 83). In this case, apoptosis was associated with cell cycle arrest at G1/S, inhibition of E2F DNA binding activity, accumulation of hypophosphorylated Rb, inhibition of Cdk2 kinase activity and an increase in p21Cip1/Waf1 transcript levels. Additional data support the assignment of apoptotic-inducing properties to NF-kappaB complexes; thus, radiation-induced apoptosis of fibroblasts from ataxia-telangiectasia (AT) patients, which exhibit a constitutive NF-kappaB-like activity, was reduced by a dominant negative IkappaBalpha mutant (84). The pro-apoptotic capability of the c-Rel protein is not shared by its viral counterpart, since both the use of a temperature-sensitive v-Rel mutant (85) and downregulation of v-Rel expression in chicken spleen cells through a tetracycline-controlled system suggest a role for v-Rel in apoptosis suppression (31, 85).

In contrast to the results obtained with c-Rel, p65/RelA acts as a potent apoptosis inhibitor. The first evidence came from the study of RelA knockout mice, which suffer from massive hepatic apoptotic death and die during embryonic life (21). These observations led to a hypothesis in which RelA drives mechanisms protecting fetal hepatocytes from apoptotic signals delivered by resident hematopoietic cells. The RelA knockout phenotype closely resembles that of c-jun-deficient mice, suggesting similar functions for RelA-containing NF-kappaB dimers and c-jun in fetal liver development.

Further evidence supports the role of RelA in apoptosis suppression. Thus, the presence of RelA has been correlated with resistance to TNF-alpha-induced apoptosis in mouse fibroblasts and macrophages (86). RelA function in this context has been associated with the induction of anti-apoptotic genes that result from the interaction of TNF-alpha with its type I receptor. As occurs with TNF-alpha, other apoptotic stimuli that induced NF-kappaB nuclear translocation such as ionizing radiation and the chemotherapeutic compound, daunorubicin, did not kill cells when NF-kappaB function was allowed (87). Stable transfection of primary mouse embryo fibroblasts or Jurkat human lymphoma cells with a dominant negative IkappaBalpha mutant that is defective in phosphorylation and thus not susceptible to degradation, rendered these cell types susceptible to TNF-alpha-induced apoptosis (88). Transgenic mice expressing a dominant negative IkappaB mutant under the control of the T cell-specific lck promoter also showed a loss of CD8+ T cells in the thymus and enhanced sensitivity to activation-induced cell death (31).