Abstract
Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays vital roles in modulating metabolism, immunity, and oncogenesis. ATF3 acts as a hub of the cellular adaptive-response network. Multiple extracellular signals, such as endoplasmic reticulum (ER) stress, cytokines, chemokines, and LPS, are connected to ATF3 induction. The function of ATF3 as a regulator of metabolism and immunity has recently sparked intense attention. In this review, we describe how ATF3 can act as both a transcriptional activator and a repressor. We then focus on the role of ATF3 and ATF3-regulated signals in modulating metabolism, immunity, and oncogenesis. The roles of ATF3 in glucose metabolism and adipose tissue regulation are also explored. Next, we summarize how ATF3 regulates immunity and maintains normal host defense. In addition, we elaborate on the roles of ATF3 as a regulator of prostate, breast, colon, lung, and liver cancers. Further understanding of how ATF3 regulates signaling pathways involved in glucose metabolism, adipocyte metabolism, immuno-responsiveness, and oncogenesis in various cancers, including prostate, breast, colon, lung, and liver cancers, is then provided. Finally, we demonstrate that ATF3 acts as a master regulator of metabolic homeostasis and, therefore, may be an appealing target for the treatment of metabolic dyshomeostasis, immune disorders, and various cancers.
Highlights
Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP response elementbinding (CREB) family, which binds to the cyclic AMP response element (CRE) in numerous promoters with the consensus sequence TGACGTCA [1, 2]
We further found that ST32da, a synthetic ATF3 inducer selected from an ATF3-specific promoter screening platform, enhances ATF3 expression to inhibit adipogenesis/lipogenesis and promote adipocyte browning by inhibiting the carbohydrateresponsive element-binding protein–stearoyl-CoA desaturase-1 axis (ChREBP-SCD-1) [43]
ATF3 plays an important role in modulating immune homeostasis, glucose and adipose tissue regulation, and cell proliferation and metastasis in breast, prostate, colon, lung, and liver cancers
Summary
Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP response elementbinding (CREB) family, which binds to the cyclic AMP response element (CRE) in numerous promoters with the consensus sequence TGACGTCA [1, 2]. Other sequences of ATF3 binding site on the target promoters are reported [3,4,5,6], including the promoter sequence of IL-12p40 (TCGACGTCT), CCL4 (TGACATCA), cyclin D1 (CCND1) (TAACGTCA), and growth arrest and DNA damage 153 (GADD153) (TTGCATCA). ATF3 can interact with proteins via its basic leucine zipper (bZIP) domain and modulate cellular functions independently of its transcriptional activity [7, 8]. The ATF3 gene consists of four exons that encode a 181-amino acid protein with a molecular weight of 22 kDa [7]. ATF3 has been demonstrated to be a transcriptional repressor by forming a homodimer
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