Distinct domains of IkappaBalpha regulate c-Rel in the cytoplasm and in the nucleus.
IkappaBalpha is a critical regulator of Rel/NF-KB-mediated gene activation. It controls the induction of NF-KB factors by retaining them in the cytoplasm and also functions in the nucleus to terminate the induction process. In this study, we show that IkappaBalpha regulates the transcriptional activity of c-Rel in the nuclear compartment. We also demonstrate that discrete functional domains of IkappaBalpha are responsible for the cytoplasmic and nuclear regulation of c-Rel. We show that the determinants for the cytoplasmic regulation of c-Rel reside in the N-terminal and central ankyrin regions of IkappaBalpha and that the N-terminal domain of IkappaBalpha is required to mask the c-Rel nuclear localization signal. Importantly, IkappaBalpha sequences necessary to regulate c-Rel in the nucleus map to its central ankyrin domain and to a few negatively charged amino acids that immediately follow in the C-terminal IkappaBalpha PEST domain. The mapping of the IkappaBalpha determinants that control the cytoplasmic and nuclear activities of c-Rel to specific regions of the molecule suggests that IkappaBalpha inhibitors could be designed to antagonize Rel/NF-kappaB activity in different subcellular compartments or at defined stages of activation.
Luque
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I
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey, Piscataway 08854-5638, USA.
Gélinas
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C
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D002645:Chickens; D002874:Chromosome Mapping; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins; D016296:Mutagenesis; D000072000:NF-KappaB Inhibitor alpha; D019913:Nuclear Localization Signals; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D019913:Nuclear Localization Signals; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha