{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Activating transcription factor 3 (ATF3) is a stress‐inducible transcription factor that functions as a central “hub” in cellular adaptive response networks. It is rapidly upregulated in response to diverse stressors—including pathogen‐derived signals, metabolic and endoplasmic reticulum stress, and nutrient deprivation—and plays multifaceted roles in regulating inflammation, cell survival, and proliferation.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In innate immune cells such as macrophages and dendritic cells, ATF3 is induced rapidly following Toll-like receptor engagement and acts as a negative regulator of proinflammatory cytokine production (for example, suppressing interleukin-6 and interleukin-12b transcription) by altering chromatin structure together with NF-κB. This function places ATF3 as an attenuator within a regulatory circuit that balances the magnitude and duration of immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In contexts of cellular stress and proteotoxic challenges, ATF3 participates in proapoptotic pathways. For instance, during conditions of proteasome inhibition or endoplasmic reticulum stress, ATF3 complexes with other transcription factors such as ATF4 to bind to the promoter of the pro-apoptotic gene NOXA, thereby facilitating stress-induced cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n ATF3 is also involved in the response to nutrient deprivation. Its delayed binding to certain target gene promoters—for example, the asparagine synthetase (ASNS) promoter—suggests that ATF3 can counterbalance the initial transcriptional activation by ATF4, functioning as a transcriptional repressor that modulates adaptive gene expression during amino acid limitation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In pancreatic β-cells, stress signals such as proinflammatory cytokines, nitric oxide, and lipotoxicity induce ATF3 expression, promoting apoptosis and contributing to β-cell loss in diabetes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, studies in fibroblasts have demonstrated that ATF3 promotes cell cycle arrest and apoptosis, in part by binding to and repressing the cyclin D1 promoter. Thus, loss of ATF3 correlates with enhanced cell proliferation and tumorigenesis, underscoring its tumor suppressor function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, ATF3 is integrated into transcriptional complexes involved in growth factor signaling. For example, in response to PDGF-BB, ATF3 cooperates with c-Jun and Sp1 to activate the erythropoietin promoter in stromal/perivascular cells, an event that may modulate tumor angiogenesis and tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, ATF3 serves as a key negative feedback regulator in innate immune signaling and an important mediator of stress-induced apoptosis and growth arrest. Through its multifaceted interactions with other transcription factors and chromatin modifiers, ATF3 fine-tunes cellular responses to inflammatory, metabolic, and proteotoxic stress, highlighting its potential as a therapeutic target in diseases such as autoimmunity, diabetes, and cancer.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mark Gilchrist, Vesteinn Thorsson, Bin Li, et al. 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