INDUCIBLE NUCLEAR EXPRESSION OF NEWLY SYNTHESIZED I-KAPPA-B-ALPHA NEGATIVELY REGULATES DNA-BINDING AND TRANSCRIPTIONAL ACTIVITIES OF NF-KAPPA-B

The transcription factor NF-kappa B is exploited by many viruses, incl uding the human immunodeficiency virus, for expression of viral genes, but its primary role appears to be in the rapid induction of cellular genes during immune and inflammatory responses. The inhibitor protein I kappa B alpha maintains NF-kappa B in an inactive form in the cytop lasms of unstimulated cells, but upon cell activation, I kappa B alpha is rapidly degraded, leading to nuclear translocation of free NF-kapp a B. However, NF-kappa B-dependent transcription of the I kappa B alph a gene leads to rapid resynthesis of the I kappa B alpha protein and i nhibition of NF-kappa B-dependent transcription. Here we demonstrate a new regulatory function of I kappa B alpha exerted on NF-kappa B in t he nuclear compartment. Although normally found in the cytoplasm, I ka ppa B alpha, newly synthesized in response to tumor necrosis factor or interleukin 1, is transported to the nucleus. In the nucleus I kappa B alpha associates with the p50 and p65 subunits of NF-kappa B, inhibi ting DNA binding of the transcription factor. Furthermore, nuclear exp ression of I kappa B alpha correlates with transcription termination o f transfected NF-kappa B-dependent luciferase genes. Following the app earance of I kappa B alpha in the nuclei of activated cells, a dramati c reduction in the amount of nuclear p50 occurs, suggesting that NF-ka ppa B-I kappa B alpha complexes are cleared from the nucleus.