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Transgenic mouse model for imaging of ATF4 translational activation-related cellular stress responses in vivo
Takao Iwawaki1,2, Ryoko Akai1,2, Takae Toyoshima2
1Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
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.
Insights
Researchers developed a novel transgenic mouse model to track the translational activation of Activating Transcription Factor 4 (ATF4) during cellular stress. This tool aids in studying ATF4
Area of Science:
- Molecular Biology
- Cellular Stress Response
- Biomedical Research
Background:
- Activating transcription factor 4 (ATF4) is crucial for cellular adaptation to stress.
- Dysregulation of ATF4 is implicated in various diseases.
- Understanding ATF4's translational control is vital for physiological and pathological insights.
Purpose of the Study:
- To develop and validate a transgenic mouse model for monitoring ATF4 translational activation.
- To assess the model's utility in detecting diverse cellular stress responses.
- To establish a tool for investigating ATF4's role in health and disease.
Main Methods:
- Development of a transgenic mouse model with a reporter system.
- In vitro, ex vivo, and in vivo validation of the reporter system's response to cellular stress.
- Evaluation of stress intensity and duration-dependent ATF4 activation.
Main Results:
- The mouse model successfully detected nutrient starvation, antiviral, ER stress, and oxidative stress responses.
- The reporter system demonstrated stress intensity-dependent activation.
- The reporter system showed stress duration-dependent activation.
Conclusions:
- The developed mouse model is effective for imaging ATF4 translational activation across multiple biological scales.
- This tool facilitates research into the physiological and pathological roles of ATF4-related stress.
- The model holds potential for developing therapeutic drugs for ATF4-associated diseases.