Abstract
Activating transcription factor 4 (ATF4) is a translationally activated protein that plays a role in cellular adaptation to several stresses. Because these stresses are associated with various diseases, the translational control of ATF4 needs to be evaluated from the physiological and pathological points of view. We have developed a transgenic mouse model to monitor the translational activation of ATF4 in response to cellular stress. By using this mouse model, we were able to detect nutrient starvation response, antivirus response, endoplasmic reticulum (ER) stress response, and oxidative stress in vitro and ex vivo, as well as in vivo. The reporter system introduced into our mouse model was also shown to work in a stress intensity-dependent manner and a stress duration-dependent manner. The mouse model is therefore a useful tool for imaging ATF4 translational activation at various levels, from cell cultures to whole bodies, and it has a range of useful applications in investigations on the physiological and pathological roles of ATF4-related stress and in the development of clinical drugs for treating ATF4-associated diseases.
Highlights
Level of phosphorylated eIF2αleads to translational induction of ATF4, and to global repression of protein synthesis[19]
UORFs of the UMAI construct are dominantly translated under normal conditions, whereas luciferase is alternatively translated under conditions of stress
By developing the UMAI construct on the basis of human ATF4 gene and introducing the construct into HeLa or NIH3T3, we were able to confirm that luciferase activity increased markedly in response to deprivation of a specific amino acid (Leu) as well as to treatments with poly(I)poly(C) nucleotide, which mimics virus infection; tunicamycin (Tun), an endoplasmic reticulum (ER) stress inducer; and sodium arsenite (ASN), an oxidative stress inducer (Fig. 3a)
Summary
Level of phosphorylated eIF2αleads to translational induction of ATF4, and to global repression of protein synthesis[19]. The physiological and pathological roles of the ISR remain to be fully understood in mammals, because there is no suitable in vivo model for studying the response at the whole-body level. We reported on our development of a transgenic mouse model for imaging ATF4-related cellular stress response. Under conditions of stress that cause phosphorylation of eIF2α, luminescence signals are generated in tissues or cells collected from the transgenic mice, as well as in the whole bodies of the mice. This mouse model is a useful tool for monitoring the ISR in vivo. By using this mouse model, we might be able to investigate the physiological and pathological roles of the ISR and to develop clinical drugs for treating ISR-associated diseases
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