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A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1α, 2α and 3α)

Oncogene volume 20, pages 1435–1444 (2001)Cite this article

Abstract

Hypoxia inducible factors (HIF1, 2 and 3), consisting of α and β subunits, play an essential role in various responses to hypoxia. Nuclear entry of α subunits is a necessary step for the formation of DNA-binding complex with β subunit, which is constitutively localized in the nucleus. We show here that the nuclear accumulation of HIF2α induced by hypoxia is mediated through a novel variant of bipartite-type nuclear localization signal (NLS) in the C-terminus of the protein, which has an unusual length of spacer sequence between two adjacent basic domains. We further show that when the ubiquitin-proteasome system was deficient or inhibited, HIF2α accumulated in the nucleus even under normoxia, also mediated through the bipartite NLS. These findings indicate that the protein stability is critical for the nuclear localization of HIF2α and hypoxia is not a necessary factor for the process. Importantly, the NLS of HIF2α is also conserved in the other HIF family members, HIF1α and HIF3α. Mutational analyses proved that the NLS mediating the nuclear localization of HIF1α is indeed bipartite-, but not monopartite-type as thought before. Our results suggest that the newly identified NLS is crucial for the functional regulation of HIF family.

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Acknowledgements

We wish to thank Dr Tetsuya Nosaka and Dr Yoshiharu Amasaki for their helpful discussions. This work was supported by a Grant-in-Aid for Special Project Research on Cancer-Bioscience 04253204 from the Ministry of Education (to M Shibuya) and a fellowship from the Japan Society for the Promotion of Science (to JC Luo).

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  1. Department of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, 108-8639, Tokyo, Japan

    Jin Cai Luo & Masabumi Shibuya

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  1. Jin Cai Luo
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  2. Masabumi Shibuya
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Luo, J., Shibuya, M. A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1α, 2α and 3α). Oncogene 20, 1435–1444 (2001). https://doi.org/10.1038/sj.onc.1204228

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