In vivo imaging of the spatiotemporal activity of the eIF2α-ATF4 signaling pathway: Insights into stress and related disorders
C Chaveroux, V Carraro, L Canaple, J Averous… - Science …, 2015 - science.org
C Chaveroux, V Carraro, L Canaple, J Averous, AC Maurin, C Jousse, Y Muranishi, L Parry…
Science signaling, 2015•science.orgThe eIF2α-ATF4 pathway is involved in cellular adaptation to stress and is dysregulated in
numerous diseases. Activation of this pathway leads to phosphorylation of the α subunit of
eukaryotic initiation factor 2 (eIF2α) and the recruitment of the transcription factor ATF4
(activating transcription factor 4) to specific CCAAT/enhancer binding protein (C/EBP)–ATF
response elements (CAREs) located in the promoters of target genes. To monitor the
spatiotemporal modulation of this pathway in living animals, we generated a novel CARE …
numerous diseases. Activation of this pathway leads to phosphorylation of the α subunit of
eukaryotic initiation factor 2 (eIF2α) and the recruitment of the transcription factor ATF4
(activating transcription factor 4) to specific CCAAT/enhancer binding protein (C/EBP)–ATF
response elements (CAREs) located in the promoters of target genes. To monitor the
spatiotemporal modulation of this pathway in living animals, we generated a novel CARE …
The eIF2α-ATF4 pathway is involved in cellular adaptation to stress and is dysregulated in numerous diseases. Activation of this pathway leads to phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) and the recruitment of the transcription factor ATF4 (activating transcription factor 4) to specific CCAAT/enhancer binding protein (C/EBP)–ATF response elements (CAREs) located in the promoters of target genes. To monitor the spatiotemporal modulation of this pathway in living animals, we generated a novel CARE-driven luciferase mouse model (CARE-LUC). These transgenic mice enable the investigation of the eIF2α-ATF4 pathway activity in the whole organism and at the tissue and cellular levels by combining imaging, luciferase assays, and immunochemistry. Using this mouse line, we showed the tissue-specific activation pattern of this pathway in response to amino acid deficiency or endoplasmic reticulum stress and the hepatic induction of this pathway in a stress-related pathology model of liver fibrosis. The CARE-LUC mouse model represents an innovative tool to investigate the eIF2α-ATF4 axis and to develop drugs targeting this important pathway in the remediation of related pathologies.
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