[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

8. Concluding remarks

We have addressed the involvement of various NF-kappaB family members in the activation of the promoters of the genes encoding two immunologically relevant molecules, the cytokine IL-2 and the IL-2Ralpha chain. We have also compiled and discussed the available evidence that links NF-kappaB complexes to the control of apoptotic responses, either as suppressors or inducers of cell death. Finally, we have reviewed the involvement of NF-kappaB proteins in IL-2 receptor signaling.

Although preserving a prominent role as a critical mediator of cellular immune regulation, the latest findings on the biology and biochemistry of NF-kappaB highlight multifunctional implications for these transcription factors in cell responses and development. NF-kappaB appears to play a dual role in apoptotic response regulation, depending on the relationship between NF-kappaB activity and key signaling molecules in cellular responses. It is expected that, as for other multifunctional mediators, future studies of NF-kappaB activity will analyze the simultaneous delivery of different signals and how they interact and complement each other at the level of gene activation and repression to elicit global responses. According to current evidence, NF-kappaB activity may be regarded as a step in signal integration. For example, at least two different signaling pathways, mediated by calcium and PKC/Ras/Raf, respectively, may act synergistically in T cells to induce NF-kappaB activation (83) . This synergy may reflect the need for two different kinases acting simultaneously on IkappaB. Phosphorylation of serines 32 and 36 of IkappaBalpha is required for its degradation and subsequent NF-kappaB nuclear translocation. Serine 32, but not serine 36, is a target for the mitogen-activated kinase, pp90rsk, which acts downstream of MAPK, MEKK-1 and MEKK-3 within a putative PKC/Ras/Raf pathway and is activated in response to PMA, LPS or okadaic acid. In addition, a constitutive Raf kinase can only activate NF-kappaB in combination with a constitutive form of calcineurin. These data suggest that IkappaBalpha receives signals from two convergent signaling pathways, mediated by Ras and Ca2+, respectively, that result in NF-kappaB activation (116).

Hence, research on the onset of gene expression by NF-kappaB transcription factors and on their functional involvement in the control of cellular responses will help to elucidate the molecular control of the cell fate.