ATF3

ATF3 Full Name

activating transcription factor 3

ATF3 Introduction

ATF3 (activating transcription factor 3) 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 1q32.3 and encodes a protein of 181 amino acids with a molecular weight of approximately 21 kDa. ATF3 is rapidly and robustly induced by a diverse array of stress signals including endoplasmic reticulum stress, oxidative stress, DNA damage, inflammatory cytokines, growth factor withdrawal, and hypoxia, establishing it as a key immediate-early stress-responsive transcription factor. Unlike most transcription factors that act as constitutive regulators, ATF3 functions as an adaptive regulator that is normally expressed at very low levels in most tissues but is rapidly upregulated in response to cellular stress. Depending on the cellular context and the nature of the stress signal, ATF3 can function as either a transcriptional activator or a repressor by forming homodimers or heterodimers with other bZIP family members including c-JUN, JUNB, JUND, C/EBPδ, and ATF2. ATF3 plays critical roles in regulating cellular metabolism, immune responses, apoptosis, cell cycle progression, and tissue repair, and its dysregulation has been implicated in various human diseases including cancer, inflammatory disorders, cardiovascular disease, diabetes, and neurodegeneration.

Figure 1. ATF3 is a negative regulator of the inflammatory response. (Jadhav K, Zhang Y. 2017)

Gene Structure and Protein Architecture
The human ATF3 gene spans approximately 9 kb and contains 4 exons. Alternative splicing generates multiple transcript variants, with the major isoforms including ATF3 (full-length) and ATF3ΔZip2 (also known as ATF3 short isoform or ATF3s), which lacks a portion of the leucine zipper domain. The full-length protein consists of 181 amino acids and contains several functionally important domains. The N-terminal region contains a transactivation domain that interacts with co-activators such as p300 and CREB-binding protein (CBP), as well as with components of the basal transcription machinery. This domain is rich in glutamine and proline residues, characteristic of activation domains in transcription factors. The central region contains a nuclear localization signal (NLS) that mediates import into the nucleus. The C-terminal region contains the basic leucine zipper (bZIP) domain, which includes a basic DNA-binding region (amino acids 130-151) that recognizes the cyclic AMP response element (CRE) consensus sequence 5'-TGACGTCA-3' and related sequences, and a leucine zipper dimerization domain (amino acids 152-181) that mediates homodimerization and heterodimerization with other bZIP proteins.

Biological Functions in Stress Response and Inflammation
ATF3 is a master regulator of the cellular adaptive response to stress, functioning to restore homeostasis following injury or insult. Upon stress stimulation, ATF3 expression is rapidly induced through multiple signaling pathways including the JNK/p38 MAPK pathway, the ER stress pathway (PERK/eIF2α/ATF4), and the DNA damage pathway (p53). Once induced, ATF3 coordinates a broad transcriptional program that modulates cell cycle progression, apoptosis, DNA repair, metabolism, and inflammation. In the context of inflammation, ATF3 functions as a negative feedback regulator that limits the magnitude and duration of inflammatory responses. ATF3 directly represses the transcription of pro-inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1β by competing with NF-κB and other transcription factors for promoter binding or by recruiting co-repressors such as HDAC1. ATF3 also regulates the expression of chemokines (CCL2, CCL5, CXCL2), adhesion molecules (ICAM1, VCAM1), and inflammatory enzymes (COX2, iNOS). ATF3 knockout mice exhibit exaggerated inflammatory responses and are more susceptible to endotoxic shock, sepsis, and autoimmune diseases. In the regulation of apoptosis, ATF3 has dual and context-dependent functions. ATF3 promotes apoptosis in some contexts by upregulating pro-apoptotic genes including PUMA, NOXA, BAX, and BIM, while suppressing anti-apoptotic genes such as BCL2 and BCL-XL. In other contexts, particularly following chronic or mild stress, ATF3 promotes cell survival by inducing cytoprotective genes including heat shock proteins, antioxidant enzymes (SOD2, catalase), and DNA repair factors (GADD45, PCNA). This context-dependent switching between pro-apoptotic and pro-survival functions is determined by the nature, intensity, and duration of the stress signal, as well as by the availability of heterodimerization partners.

Alternate Names for ATF3

ATF3; activating transcription factor 3; cyclic AMP-dependent transcription factor ATF-3; cAMP-dependent transcription factor ATF-3;

• 1.Jadhav K, Zhang Y. Activating transcription factor 3 in immune response and metabolic regulation. Liver Res 1: 96–102[EB/OL].(2017)