title: Critical role of N-terminal end-localized nuclear export signal in regulation of activating transcription factor 2 (ATF2) subcellular localization and transcriptional activity.
abstract: Activating transcription factor 2 (ATF2) belongs to the basic leucine zipper family of transcription factors. ATF2 regulates target gene expression by binding to the cyclic AMP-response element as a homodimer or a heterodimer with c-Jun. Cytoplasmic localization of ATF2 was observed in melanoma, brain tissue from patients with Alzheimer disease, prostate cancer specimens, and ionizing radiation-treated prostate cancer cells, suggesting that alteration of ATF2 subcellular localization may be involved in the pathogenesis of these diseases. We previously demonstrated that ATF2 is a nucleocytoplasmic shuttling protein, and it contains two nuclear localization signals in the basic region and one nuclear export signal (NES) in the leucine zipper domain (named LZ-NES). In the present study, we demonstrate that a hydrophobic stretch in the N terminus, (1)MKFKLHV(7), also functions as an NES (termed N-NES) in a chromosome region maintenance 1 (CRM1)-dependent manner. Mutation of both N-NES and LZ-NES results in a predominant nuclear localization, whereas mutation of each individual NES only partially increases the nuclear localization. These results suggest that cytoplasmic localization of ATF2 requires function of at least one of the NESs. Further, mutation of N-NES enhances the transcriptional activity of ATF2, suggesting that the novel NES negatively regulates the transcriptional potential of ATF2. Thus, ATF2 subcellular localization is probably modulated by multiple mechanisms, and further understanding of the regulation of ATF2 subcellular localization under various pathological conditions will provide insight into the pathophysiological role of ATF2 in human diseases.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Chih-Chao
authors.initials: CC
authors.lastname: Hsu
authors.forename: Chang-Deng
authors.initials: CD
authors.lastname: Hu
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D016350:Leucine Zippers; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D049790:Nuclear Export Signals; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D049790:Nuclear Export Signals