[NF-kappaB tumorigenesis and drug developement]

NF-kappaB, a collective name of dimeric transcription factors, is composed of members of the Rel family proteins that recognize and bind a specific DNA sequence. It is normally sequestered in the cytoplasm of non-stimulated cells by associating with a family of inhibitor proteins called IkappaBs. Exposure of cells to a variety of extra-and intra-cellular stimuli leads to the rapid proteolytic degradation of IkappaBs, which frees NF-kappaBs allowing them to translocate to the nucleus where it regulates gene transcription. NF-kappaB is involved in a lot of physiological processes such as immunity, inflammation, cell proliferation, apoptosis and even tumorigenesis by regulating the transcription of a larger number of genes. This review introduces the various mechanisms of NF-kappaB activation including a recently reported alternative activation pathway mediated by lymphotoxin alpha/beta, B cell activating factor and CD40 ligand. The signal transduction pathway leading to NF-kappaB activation via IKK in response to proinflammatory factors like TNF-alpha and IL-1 is addressed in more detail concerning the regulation of IKK activity, mechanism of IkappaB degradation and regulation of transactivation activity of NF-kappaB on different levels. Considering the important role of NF-kappaB in cell proliferation and regulation of various genes participating in apoptosis, the involvement of NF-kappaB in tumorigenesis and drug screening is also discussed.