ATF1

ATF1 Full Name

activating transcription factor 1

ATF1 Introduction

ATF1 (activating transcription factor 1) is a member of the activating transcription factor/cAMP-responsive element-binding protein (ATF/CREB) family of basic leucine zipper (bZIP) transcription factors. The gene is located on chromosome 12q13.12 and encodes a protein of 271 amino acids with a molecular weight of approximately 30 kDa. ATF1 is ubiquitously expressed in human tissues, with particularly high levels in the brain, heart, testis, and lymphocytes. The protein functions as a transcription factor that binds to the cyclic AMP response element (CRE) consensus sequence 5'-TGACGTCA-3' as a homodimer or as a heterodimer with other bZIP family members including CREB1 and CREM. ATF1 is activated by phosphorylation at Ser-63 (equivalent to Ser-133 in CREB) by multiple protein kinases including protein kinase A (PKA), Ca²⁺/calmodulin-dependent protein kinases (CaMKs), mitogen-activated protein kinases (MAPKs), and protein kinase C (PKC). Upon activation, ATF1 regulates the expression of genes involved in cell proliferation, differentiation, survival, metabolism, and circadian rhythms. ATF1 has been implicated in various physiological processes including learning and memory, cellular stress responses, and immune function. Dysregulation of ATF1 has been associated with several human diseases, including cancer (particularly Ewing sarcoma and salivary gland tumors), cardiovascular disease, neurological disorders, and metabolic diseases.

Figure 1. Schematic structure of ATF1.

Gene Structure and Protein Architecture
The human ATF1 gene spans approximately 4.5 kb and contains 8 exons. Alternative splicing generates multiple transcript variants, with the major isoform encoding a protein of 271 amino acids. ATF1 contains several functionally important domains characteristic of the ATF/CREB family. The N-terminal region contains the activation domain, which includes a kinase-inducible domain (KID) that contains the phosphorylation site Ser-63 (corresponding to Ser-133 in CREB). This domain interacts with the KIX domain of CREB-binding protein (CBP) and p300, recruiting these transcriptional co-activators to promote gene expression. The phosphorylation of Ser-63 is essential for this interaction and for ATF1 transcriptional activity. The KID domain is flanked by glutamine-rich regions that also contribute to transcriptional activation. The central region contains a glutamine-rich domain that may mediate protein-protein interactions and contribute to transcriptional activation. The C-terminal region contains the basic leucine zipper (bZIP) domain (approximately amino acids 200-271), which consists of a basic DNA-binding region rich in lysine and arginine residues that directly contacts DNA, and a leucine zipper dimerization domain composed of four to five heptad repeats of leucine residues that form an amphipathic alpha-helix, allowing coiled-coil interactions with other bZIP proteins.

Immune and Inflammatory Regulatory Roles of ATF1
Beyond its metabolic and developmental functions, ATF1 acts as a key modulator of immune activation and inflammatory signal transduction in multiple human tissues. ATF1 participates in regulating the transcription of critical pro-inflammatory cytokines, chemokines, and immune response genes, serving as a positive regulator of inflammatory cascade activation. Under pathological stimulation, activated ATF1 synergizes with NF-κB and AP-1 signaling pathways to amplify inflammatory responses, promoting immune cell recruitment and tissue inflammatory injury. In chronic inflammatory conditions, sustained ATF1 hyperactivation maintains a persistent pro-inflammatory microenvironment, accelerating tissue fibrosis and organ dysfunction. Conversely, basal ATF1 activity is required for maintaining normal immune cell development and host defense responses against pathogen invasion. This dual regulatory role enables ATF1 to balance physiological immune defense and pathological inflammatory damage in human bodies.

Alternate Names for ATF1

ATF1; activating transcription factor 1; TREB36; EWS-ATF1; FUS/ATF-1; cyclic AMP-dependent transcription factor ATF-1; cAMP-dependent transcription factor ATF-1;