Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha.

K Brown, S Park, T Kanno… - Proceedings of the …, 1993 - National Acad Sciences
K Brown, S Park, T Kanno, G Franzoso, U Siebenlist
Proceedings of the National Academy of Sciences, 1993National Acad Sciences
The NK-kappa B transcription factor complex is sequestered in the cytoplasm by the
inhibitory protein I kappa B-alpha (MAD-3). Various cellular stimuli relieve this inhibition by
mechanisms largely unknown, leading to NF-kappa B nuclear localization and
transactivation of its target genes. It is demonstrated here with human T lymphocytes and
monocytes that different stimuli, including tumor necrosis factor alpha and phorbol 12-
myristate 13-acetate, cause rapid degradation of I kappa B-alpha, with concomitant …
The NK-kappa B transcription factor complex is sequestered in the cytoplasm by the inhibitory protein I kappa B-alpha (MAD-3). Various cellular stimuli relieve this inhibition by mechanisms largely unknown, leading to NF-kappa B nuclear localization and transactivation of its target genes. It is demonstrated here with human T lymphocytes and monocytes that different stimuli, including tumor necrosis factor alpha and phorbol 12-myristate 13-acetate, cause rapid degradation of I kappa B-alpha, with concomitant activation of NF-kappa B, followed by a dramatic increase in I kappa B-alpha mRNA and protein synthesis. Transfection studies reveal that the I kappa B-alpha mRNA and the encoded protein are potently induced by NF-kappa B and by homodimers of p65 and of c-Rel. We propose a model in which NF-kappa B and I kappa B-alpha mutually regulate each other in a cycle: saturating amounts of the inhibitory I kappa B-alpha protein are destroyed upon stimulation, allowing rapid activation of NF-kappa B. Subsequently, I kappa B-alpha mRNA and protein levels are quickly induced by the activated NF-kappa B. This resurgence of I kappa B-alpha protein acts to restore an equilibrium in which NF-kappa B is again inhibited.
National Acad Sciences