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. O ur previous studies identified discrete functional domains in I kappa B alp ha responsible for the cytoplasmic and nuclear regulation of c-Rel, Determi nants necessary for regulating c-Rel in the nucleus mapped to the central a nkyrin domain of I kappa-B alpha and a fen negatively-charged amino acids t hat follow in the C-terminal PEST region. In contrast, sequences involved i n 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 t he 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 p 40/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 localizati on of Rel/NF-kappa B dimers, Given the implication of deregulated NF-kappa B activity in hematopoietic and solid tumors, our findings predict that cer tain alterations in this domain of I kappa B alpha may have severe biologic al repercussions.