Kappa B site-dependent induction of gene expression by diverse inducers of nuclear factor kappa B requires Raf-1.
The transcription factor nuclear factor kappa B (NF-kappa B) is sequestered in the cytoplasm of most cell types where it is complexed with its inhibitor (I kappa B). A large variety of agents, including growth factors, the tumor promoter phorbol 12-myristate 13-acetate, and the cytokine tumor necrosis factor alpha, initiate signal transduction pathways that converge upon the NF-kappa B-I kappa B complex, resulting in the dissociation of I kappa B and the translocation of NF-kappa B to the nucleus. It has been demonstrated that the phosphorylation of I kappa B is associated with NF-kappa B activation, although the kinase(s) responsible for this process in vivo remain unknown. Here we demonstrate that expression of activated forms of the GTP-binding protein Ras or of the serine/threonine kinase Raf-1 results in the activation of transcription specifically through kappa B sites. This activation appears to be dependent on NF-kappa B, since co-expression of I kappa B alpha eliminates both Ras- and Raf-1-induced transcription. In addition, through the use of a dominant negative form of Raf-1, we show that Raf-1 is a common component utilized by multiple inducers in kappa B site-driven gene expression. These results illuminate a signal transduction pathway in which NF-kappa B/Rel family members participate and also implicate a pathway responsible for kappa B site-dependent gene expression during cell growth and in immune and inflammatory responses.
Finco
T S
TS
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599.
Baldwin
A S
AS
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000378:metabolism; D005786:Gene Expression Regulation; D016325:HIV Long Terminal Repeat; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000378:metabolism; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D011994:Recombinant Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015500:Chloramphenicol O-Acetyltransferase; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D015689:Oncogene Protein p21(ras)