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Table 3 ATF6 signalling in tissue homeostasis and pathogenesis

From: A lifetime of stress: ATF6 in development and homeostasis

Tissue Model Effect Reference
Protective Role of ATF6 Signalling
 Heart Mouse model of myocardial ischemia/reperfusion damage
KO of ATF6 in mice
When compared to wild-type tissue, ATF6 KO mouse cardiac tissue exhibited increased damage upon ischemia/reperfusion. Mechanistically, ATF6 upregulates oxidative stress genes, such as catalase, to exert cardioprotective effects in this context [49]
 Kidney Tunicamycin-induced cytotoxicity in rat-derived glomerular epithelial cells (GECs) Calcium-independent phospholipase A2γ (iPLA2γ) is protective against GEC injury. ATF6 contributes to iPLA2γ-mediated cytoprotection [50]
 Brain Short-form ATF6 KI in forebrain neurons of mice (tamoxifen-inducible activation)
Experimental model of stroke induced by middle cerebral artery occlusion
Forced activation of ATF6 reduced infarct volume and improved functional outcome following 24 h post-model induction [51]
R6/2 mouse model of Huntington’s disease Derepression of ATF6 was associated with early neuroprotection in this model of Huntington’s disease [52]
Kainate-induced neurotoxicity in hippocampi of mice
Kainate induced pronounced neuronal death in hippocampal CA3 region of ATF6α-KO mice. Hence, ATF6α protects against kainate-induced neurotoxicity in mice [53]
 Pancreas/Liver Diet-induced obese mice
KOt of ATF6α
ATF6α protects pancreatic β-cells from endoplasmic reticulum stress [55]
Zebrafish model of endoplasmic reticulum stress and fatty liver disease
Depletion of active ATF6 through mutation in site-1 protease gene (mbtps1) or atf6 morpholino injection
ATF6 protects against hepatic steatosis following tunicamycin-induced acute endoplasmic reticulum stress [57]
Pathological Role of ATF6 Signalling
 Liver OE of activated form of ATF6α in human hepatocellular carcinoma cell line (HLF) ATF6α maylead to hepatocarcinogenesis by directly
and indirectly regulating a broad range of genes associated with transformation
Zebrafish model of endoplasmic reticulum stress and fatty liver disease; Depletion of active ATF6 through mutation in site-1 protease gene (mbtps1) or atf6 morpholino injection ATF6 ➔ hepatic steatosis resulting from chronic endoplasmic reticulum stress [57]
 Squamous Epithelium Quiescent human squamous carcinoma
cells (D-HEp3 cells)
KD of ATF6α expression in D-Hep3 cells using chick chorioallantoic membrane and nude mice for xenograft studies
ATF6α ➔ dormant cell survival, adaptation of dormant cells to chemotherapy, nutritional stress and the in vivo microenvironment
ATF6α-Rheb-mTOR signalling ➔ survival and adaptation of carcinoma cells
 Pancreas Diet-induced obese mice
KO of ATF6α
ATF6α ➔ development of hyperlipidaemia and insulin resistance in mouse model of diabetes [55]
Otsuka Long Evans Tokushima Fatty rat model of type II diabetes ↑ ATF6 in pancreatic islets in diseased rats;
ATF6 ➔ ↓insulin levels
  1. Key: ATF6 activating transcription factor 6, GEC glomerular epithelial cell, iPLA2γ calcium-independent phospholipase A2γ, KD knockdown, KI knockin, KO knockout