title: The metalloid arsenite induces nuclear export of Id3 possibly via binding to the N-terminal cysteine residues.
abstract: Ids are versatile transcriptional repressors that regulate cell proliferation and differentiation, and appropriate subcellular localization of the Id proteins is important for their functions. We previously identified distinct functional nuclear export signals (NESs) in Id1 and Id2, but no active NES has been reported in Id3. In this study, we found that treatment with the stress-inducing metalloid arsenite led to the accumulation of GFP-tagged Id3 in the cytoplasm. Cytoplasmic accumulation was impaired by a mutation in the Id3 NES-like sequence resembling the Id1 NES, located at the end of the HLH domain. It was also blocked by co-treatment with the CRM1-specific nuclear export inhibitor leptomycin B (LMB), but not with the inhibitors for mitogen-activated protein kinases (MAPKs). Importantly, we showed that the closely spaced N-terminal cysteine residues of Id3 interacted with the arsenic derivative phenylarsine oxide (PAO) and were essential for the arsenite-induced cytoplasmic accumulation, suggesting that arsenite induces the CRM1-dependent nuclear export of Id3 via binding to the N-terminal cysteines. Finally, we demonstrated that Id3 significantly repressed arsenite-stimulated transcription of the immediate-early gene Egr-1 and that this repression activity was inversely correlated with the arsenite-induced nuclear export. Our results imply that Id3 may be involved in the biological action of arsenite.
authors.affiliation: Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. hkurooka@u-fukui.ac.jp
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kurooka
authors.forename: Manabu
authors.initials: M
authors.lastname: Sugai
authors.forename: Kentaro
authors.initials: K
authors.lastname: Mori
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Yokota
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D028884:Karyopherins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D049790:Nuclear Export Signals; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic; D014162:Transfection; D000097606:Exportin 1 Protein
chemical_list: D018053:Arsenites; D003545:Cysteine; D049452:Green Fluorescent Proteins; D051796:Inhibitor of Differentiation Proteins; D028884:Karyopherins; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D017670:Sodium Compounds; D000097606:Exportin 1 Protein; C067679:Idb3 protein, mouse; C017947:sodium arsenite