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Official Full Name
activating transcription factor 3
Activating transcription factor 3 is a member of the mammalian activation transcription factor/cAMP responsive element-binding (CREB) protein family of transcription factors. Multiple transcript variants encoding two different isoforms have been found for this gene. The longer isoform represses rather than activates transcription from promoters with ATF binding elements. The shorter isoform (deltaZip2) lacks the leucine zipper protein-dimerization motif and does not bind to DNA, and it stimulates transcription presumably by sequestering inhibitory co-factors away from the promoter. It is possible that alternative splicing of the ATF3 gene may be physiologically important in the regulation of target genes.
ATF3; activating transcription factor 3; cyclic AMP-dependent transcription factor ATF-3; cAMP-dependent transcription factor ATF-3; FLJ41705; zgc:55526

ATF3 (activating transcription factor 3) plays an important role in regulating cell proliferation, apoptosis, inflammation, immune homeostasis, and differentiation of organs and tissues. For example, in patients with prostate cancer, ATF3 accelerates tumor cell apoptosis to achieve anticancer effects. Previous studies have shown that ATF3 is a fast-response gene in the early stage of stress and is stably expressed at low levels in cells under normal conditions. However, certain stimuli such as reactive oxygen species, ultraviolet stimuli, myocardial ischemia, hypoxic state, and even the use of certain drugs such as insulin, doxorubicin, etc., can increase their transient expression, especially in myocardial tissue.

During the embryonic period, there is a large amount of BMP10 in the blood circulation, which belongs to one of the TGF-β superfamily members and is critical for cardiac development, especially myocardial tissue. Some researchers have hypothesized that there is a BMP10/ATF3 signaling pathway in myocardial tissue (this signaling pathway is important in regulating immune responses and cardiovascular development). There is an ATF/CREB binding domain regulated by the Smad1 to Smad4 molecule in the TGF-β/BMP10 reaction domain. By continuously detecting the BMP10 concentration and ATF3 expression levels in the blood circulation of the embryo during and after the embryo, they found that their concentrations gradually increased with the development of the heart. And in the BMP10 gene overexpressing mice, the ATF3 content was significantly increased. Therefore, ATF3 is considered to be an important gene highly related to cardiovascular development.

ATF3's Auto-Inhibition Loop

According to Koivisto et al, ATF3 is a stress-inducible gene that is widely expressed in rat myocardial tissue under pressure-induced induction and involves multiple signaling pathways such as MAPK, NF-κB, JNK, and cAMP-PKA. The study found that ATF3 expression is activated by a variety of stress signals, and its expression in myocardial tissue is often abnormally elevated.

Under the conditions of endothelin-1 (ET-1) stimulation, the MAPK signaling pathway is activated in the heart, which gradually leads to cardiac hypertrophy and ventricular remodeling. At the same time, ATF3 is effectively induced, which protects the heart by inhibiting the expression of various hypertrophy molecules. In the body, the expression of ATF3 is regulated by various factors, such as various signal molecules, growth factors, and microRNAs. However, in recent years, Tindall et al. proposed that there is an autorepression loop in ATF3, that is, there is an auto-feedback system in ATF3.

Figure 1. Signal transduction pathway of ATF3 protecting MIRI via TLR-4/NF-κB-mediated inflammation. (Yang, et al. 2015).

Previous studies have demonstrated that ATF3 may inhibit its expression by binding to the TATA box of its downstream target promoter, however, it is difficult to detect its expression status in an endogenous system. Tindall examined the relationship between ATF3 mRNA expression and protein expression in myocardial tissue. The results showed that the ATF3 gene gradually increased after ET-1 stimulation, and then gradually decreased after reaching the peak at 30 min and decreased to baseline at 4 h. However, the expression curve of its protein is relatively delayed, so he speculated that the protein product of ATF3 can inhibit its mRNA expression. Tindall later confirmed this hypothesis through experimental methods of mathematical modeling, in which ATF3 has an autoinhibitory loop to regulate the expression of its own genes.

ATF3 and Cardiovascular Disease

Brooks et al. used ATF3 knockout mice and wild mice as subjects to calculate myocardial infarct size by simulated ischemia-reperfusion model and RT-PCR and Western blot. The results showed that in the case of cardiac ATF3 knockout, the infarct size of myocardial tissue increased significantly, and inflammatory factors and adhesion molecules such as IL-6, IL-12β, ICAM1, etc. increased significantly. The results indicate that ATF3 has a protective effect on the heart during ischemia.

Cardiac hypertrophy is a chronic adaptive compensatory mechanism of stress and volume overload in the heart. It is a complex pathophysiological process mediated by various neurohumoral factors. Studies have shown that ATF3 knockout can aggravate stress-induced cardiac hypertrophy and myocardial fibrosis, further impairing cardiac function. On the other hand, ATF3 can inhibit MAPK, JNK, PI3K-AKT and other signaling pathways to weaken the development of cardiac hypertrophy. The above studies confirm that ATF3 is an effective protective gene for cardiac hypertrophy. However, Koren et al. believe that the expression of ATF3 in the heart can promote the rise of blood pressure and the occurrence and development of cardiac hypertrophy, causing deterioration of cardiac function, contrary to the above viewpoint.

Heart failure is the end stage of various cardiovascular diseases, accompanied by the production of autophagy in the development of heart failure. Autophagy is divided into three methods: macroautophagy, microautophagy, and chaperone-mediated autophagy. Lin et al. used ATF3 knockout mice and WT mice as subjects to induce heart failure by transverse aortic banding (TAB). The results of echocardiography and Western blot showed that the cardiac function of the ATF3 knockout group was significantly worse and the expression of c-caspase-3 was increased. Tert-butyl hydroquinone (tBHQ) is a drug that promotes ATF3 expression. After over-expression of ATF3 in mouse hearts by transfection of ATF3 with adenovirus or intravenous injection of tBHQ, the above situation was significantly reversed. These results suggest that the absence of ATF3 can aggravate stress-induced heart failure.


  1. Koivisto, E., Jurado, A. A., Moilanen, A. M., Tokola, H., Aro, J., & Pennanen, H., et al. (2014). Characterization of the regulatory mechanisms of activating transcription factor 3 by hypertrophic stimuli in rat cardiomyocytes. Plos One, 9(8), e105168.
  2. Tindall, M. J., & Clerk, A. (2014). Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for mirnas in immediate early gene regulation. PLoS Computational Biology, 10,5(2014-5-8), 10(5), e1003597.
  3. Brooks, A. C., Singh, M., Guo, Y., Mccracken, J., Xuan, Y. T., & Srivastava, S., et al. (2014). Endoplasmic reticulum stress-dependent activation of atf3 mediates the late phase of ischemic preconditioning. Journal of Molecular & Cellular Cardiology, 76, 138-147.
  4. Lilach, K., Ofer, E., Izhak, K., Hai, T., & Ami, A. (2013). Adult cardiac expression of the activating transcription factor 3, atf3, promotes ventricular hypertrophy. Plos One, 8(7), e68396.
  5. Lin, H., Li, H. F., Chen, H. H., Lai, P. F., Juan, S. H., & Chen, J. J., et al. (2014). Activating transcription factor 3 protects against pressure-overload heart failure via the autophagy molecule beclin-1 pathway. Molecular Pharmacology, 85(5), 682.
  6. Yang, C. J., Yang, J., Fan, Z. X., & Yang, J. (2015). Activating transcription factor 3 ‑ an endogenous inhibitor of myocardial ischemia-reperfusion injury (review). Molecular Medicine Reports, 104(7), 566-7.