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.
Highlights
Alteration of Activating transcription factor 2 (ATF2) subcellular localization is involved in multiple human diseases
N-terminal Domain Promotes ATF2 Nuclear Export in chromosome region maintenance 1 (CRM1)-dependent Manner—We previously demonstrated that ATF2 contains an nuclear export signal (NES) in the leucine zipper region, which, in conjunction with two nuclear localization signals (NLSs) in the basic region, regulates ATF2 nucleocytoplasmic shuttling (Fig. 1A)
We observed that deletion of the N-terminal domain (NTD) of ATF2 increased nuclear localization of Jun-ATF2 heterodimers [33], whereas overexpressed full-length ATF2 was predominantly localized in the cytoplasm despite possession of the two NLS motifs [19]
Summary
Alteration of ATF2 subcellular localization is involved in multiple human diseases. Results: A second nuclear export signal was identified in the most N-terminal end of ATF2. 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). The transcriptional activity of ATF2 is regulated by an intramolecular interaction between the N-terminal transactivation domain and the bZIP domain [17]. This is largely based on the observation that the activity of ATF2 is limited when it is exogenously expressed without coexpression with its dimerization partners or coactivators [17,18,19,20]. We have found that ATF2 is a nucleocytoplasmic shuttling protein with a nuclear export signal (NES) and two nuclear localization signals (NLSs) in its leucine zipper and basic region, respectively [19].
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