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N-terminal determinants of IκBα necessary for the cytoplasmic regulation of c-Rel

Oncogene volume 19, pages 1239–1244 (2000)Cite this article

Abstract

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

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Acknowledgements

We are very grateful to H Bose (University of Texas, Austin, TX, USA) for the IκBα cDNA clone, N Rice (ABL-NCI, Frederick, MD, USA) for anti-p40/IκBα antibody #1275, T Gilmore (Boston University, Boston, MA, USA) for the c-rel cDNA, and K Nakayama (Kanazawa University, Japan) for pIL6κBCAT. We thank J Bash, LC Edelstein and M Hannink for fruitful discussions during the course of this work and B Rayet for assistance with the correction of the proofs. This work was supported by National Institutes of Health grant CA-54999 from the National Cancer Institute (C Gélinas) and by the New Jersey Commission on Science and Technology. I Luque was supported by a post-doctoral fellowship from the International Human Frontier Science Program. C Chen was supported by a post-doctoral fellowship from the New Jersey Commission on Cancer Research and by the Foundation of UMDNJ.

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  1. Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, Piscataway, 08854-5638, New Jersey, NJ, USA

    Ignacio Luque, Wei-xing Zong, Cailin Chen & Céline Gélinas

  2. Department of Biochemistry, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, Piscataway, 08854-5638, New Jersey, NJ, USA

    Wei-xing Zong & Céline Gélinas

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Luque, I., Zong, Wx., Chen, C. et al. N-terminal determinants of IκBα necessary for the cytoplasmic regulation of c-Rel. Oncogene 19, 1239–1244 (2000). https://doi.org/10.1038/sj.onc.1203400

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