PMID:17430897

Citation	Lin, Q, Weis, S, Yang, G, Weng, YH, Helston, R, Rish, K, Smith, A, Bordner, J, Polte, T, Gaunitz, F and Dennery, PA (2007) Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress. J. Biol. Chem. 282:20621-33
Abstract	Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is an integral membrane protein of the smooth endoplasmic reticulum. However, we detected an HO-1 immunoreactive signal in the nucleus of cultured cells after exposure to hypoxia and heme or heme/hemopexin. Under these conditions, a faster migrating HO-1 immunoreactive band was enriched in nuclear extracts, suggesting that HO-1 was cleaved to allow nuclear entry. This was confirmed by the absence of immunoreactive signal with an antibody against the C terminus and the lack of a C-terminal sequence by gas chromatographymass spectrometry. Incubation with leptomycin B prior to hypoxia abolished nuclear HO-1 and the faster migrating band on Western analysis, suggesting that this process was facilitated by CRM1. Furthermore, preincubation with a cysteine protease inhibitor prevented nuclear entry of green fluorescent protein-labeled HO-1, demonstrating that protease-mediated C-terminal cleavage was also necessary for nuclear transport of HO-1. Nuclear localization was also associated with reduction of HO activity. HO-1 protein, whether it was enzymatically active or not, mediated activation of oxidant-responsive transcription factors, including activator protein-1. Nevertheless, nuclear HO-1 protected cells against hydrogen peroxide-mediated injury equally as well as cytoplasmic HO-1. We speculate that nuclear localization of HO-1 protein may serve to up-regulate genes that promote cytoprotection against oxidative stress.
Links	PubMed Online version:10.1074/jbc.M607954200
Keywords	Active Transport, Cell Nucleus/drug effects; Active Transport, Cell Nucleus/physiology; Animals; Antibiotics, Antineoplastic/pharmacology; Cell Hypoxia/physiology; Cell Line, Tumor; Cell Nucleus/enzymology; Cell Nucleus/genetics; Fatty Acids, Unsaturated/pharmacology; Heme/pharmacology; Heme Oxygenase-1/genetics; Heme Oxygenase-1/metabolism; Hemopexin/pharmacology; Humans; Hydrogen Peroxide; Karyopherins/genetics; Karyopherins/metabolism; Mice; NIH 3T3 Cells; Oxidants; Oxidative Stress/drug effects; Oxidative Stress/physiology; Protein Structure, Tertiary/physiology; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism; Transcription Factor AP-1/genetics; Transcription Factor AP-1/metabolism; Up-Regulation/drug effects; Up-Regulation/physiology
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