N-terminal determinants of I kappa B alpha necessary for the cytoplasmic regulation of c-Rel.

I kappa B alpha is a dual regulator of Rel/NF-kappa B transcription factors. I kappa B alpha retains inactive NF-kappa B dimers in the cytoplasm, and inhibits their DNA-binding and transcriptional activities in the nucleus. Our previous studies identified discrete functional domains in I kappa B alpha responsible for the cytoplasmic and nuclear regulation of c-Rel. Determinants necessary for regulating c-Rel in the nucleus mapped to the central ankyrin domain of I kappa B alpha and a few negatively-charged amino acids that follow in the C-terminal PEST region. In contrast, sequences involved in the cytoplasmic regulation of c-Rel reside in the N-terminal and central ankyrin domains of I kappa B alpha. Here, we present a refined mapping of the N-terminal determinants of I kappa B alpha necessary for the cytoplasmic regulation of c-Rel homodimers. We demonstrate that amino acids 48 - 58 in p40/I kappa B alpha are essential to block the nuclear localization of c-Rel dimers. These data define a region of I kappa B alpha that may be required for optimal masking of the c-Rel NLS, or for the nuclear export of c-Rel/I kappa B alpha complexes. These findings highlight a novel function for the N-terminus of I kappa B alpha in the control of the subcellular localization of Rel/NF-kappa B dimers. Given the implication of deregulated NF-kappa B activity in hematopoietic and solid tumors, our findings predict that certain alterations in this domain of I kappa B alpha may have severe biological repercussions.