The FOXO Transcription Factor DAF-16 Bypasses ire-1 Requirement to Promote Endoplasmic Reticulum Homeostasis

Safra, Modi; Fickentscher, Rolf; Levi-Ferber, Mor; Danino, Yehuda M.; Haviv-Chesner, Anat; Hansen, Malene; Juven‐Gershon, Tamar; Weiß, Matthias; Henis-Korenblit, Sivan

doi:10.1016/j.cmet.2014.09.006

Cited by 30 publications

(32 citation statements)

References 44 publications

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“…In response to stress DAF-2/DAF-16 and GCN-2 also regulate the endoplasmic reticulum (ER) stress response [37, 50, 52], resulting in an upregulation of the ER-specific heat shock protein, HSP-4, one of two C. elegans heat shock proteins homologous to hsp70 proteins in mammals. To delineate the role of the ER stress response in AIN, we tested the mutants ire-1, xbp-1 and hsp-4 .…”

Section: Resultsmentioning

confidence: 99%

“…We propose a model which explains all our data in Figure 6. Isoflurane induces the two highly conserved signaling pathways by inhibition of mitochondrial function, similar to their known responses to a variety of other environmental stresses like heat shock, caloric restriction, and hypoxia [52–54]. Others have shown that mitochondrial ROS plays an important role in AIN [22].…”

Section: Discussionmentioning

confidence: 99%

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The genetics of isoflurane-induced developmental neurotoxicity

Brockway

Gentry

et al. 2017

Neurotoxicology and Teratology

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Introduction Neurotoxicity induced by early developmental exposure to volatile anesthetics is a characteristic of organisms across a wide range of species, extending from the nematode C. elegans to mammals. Prevention of anesthetic-induced neurotoxicity (AIN) will rely upon an understanding of its underlying mechanisms. However, no forward genetic screens have been undertaken to identify the critical pathways affected in AIN. By characterizing such pathways, we may identify mechanisms to eliminate isoflurane induced AIN in mammals. Methods Chemotaxis in adult C. elegans after larval exposure to isoflurane was used to measure AIN. We initially compared changes in chemotaxis indices between classical mutants known to affect nervous system development adding mutants in response to data. Activation of specific genes was visualized using fluorescent markers. Animals were then treated with rapamycin or preconditioned with isoflurane to test effects on AIN. Results Forty-four mutations, as well as pharmacologic manipulations, identified two pathways, highly conserved from invertebrates to humans, that regulate AIN in C. elegans. Activation of one stress-protective pathway (DAF-2 dependent) eliminates AIN, while activation of a second stress-responsive pathway (endoplasmic reticulum (ER) associated stress) causes AIN. Pharmacologic inhibition of the mechanistic Target of Rapamycin (mTOR) blocks ER-stress and AIN. Preconditioning with isoflurane prior to larval exposure also inhibited AIN. Discussion Our data are best explained by a model in which isoflurane acutely inhibits mitochondrial function causing activation of responses that ultimately lead to ER-stress. The neurotoxic effect of isoflurane can be completely prevented by manipulations at multiple points in the pathways that control this response. Endogenous signaling pathways can be recruited to protect organisms from the neurotoxic effects of isoflurane.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The genetics of isoflurane-induced developmental neurotoxicity

Brockway

Gentry

et al. 2017

Neurotoxicology and Teratology

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“…2). It was also demonstrated that activated FOXO3, similarly to DAF-16, protects ER function and maintains secretory protein metabolism independently of the IRE1 UPR pathway in mammalian cells (Safra et al, 2014).…”

Section: Er Stressmentioning

confidence: 98%

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

Saavedra‐García

Nichols

Mahmud

et al. 2018

Molecular and Cellular Endocrinology

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Keywords:Fatty acids Cancer Lipid metabolism FOXO3 FOXM1 AKT/PI3K pathway a b s t r a c t Obesity and cachexia represent divergent states of nutritional and metabolic imbalance but both are intimately linked to cancer. There is an extensive overlap in their signalling pathways and molecular components involved such as fatty acids (FAs), which likely play a crucial role in cancer. Forkhead box (FOX) proteins are responsible of a wide range of transcriptional programmes during normal development, and the FOXO3-FOXM1 axis is associated with cancer initiation, progression and drug resistance.Free fatty acids (FFAs), FA synthesis and b-oxidation are associated with cancer development and progression. Meanwhile, insulin and some adipokines, that are up-regulated by FAs, are also involved in cancer development and poor prognosis. In this review, we discuss the role of FA metabolism in cancer and how FA metabolism integrates with the FOXO3-FOXM1 axis. These new insights may provide leads to better cancer diagnostics as well as strategies for tackling cancer development, progression and drug resistance.

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“…63 ). XBP1 also controls the expression of the hexosamine biosynthetic pathway ( 102 ) and negatively regulates the levels of the transcription factor FOXO1, thereby affecting energy control and glucose metabolism, both controlled by genes dependent on FOXO1-mediated transcription ( 103 ) as well as ER homeostasis ( 104,105 ). This provides a potentially cancer-relevant link between IRE1 and PERK signals, as both stress sensors can regulate the functionality of FOXO transcription factors ( 16 ).…”

Section: Tumor Microenvironment and Er Stressmentioning

confidence: 99%

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

2015

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Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many human diseases, including cancers. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. The UPR has emerged as a major pathway in remodeling cancer gene expression, thereby either preventing cell transformation or providing an advantage to transformed cells. UPR sensors are highly regulated by the formation of dynamic protein scaffolds, leading to integrated reprogramming of the cells. Herein, we describe the regulatory mechanisms underlying UPR signaling upon cell intrinsic or extrinsic challenges, and how they engage cell transformation programs and/or provide advantages to cancer cells, leading to enhanced aggressiveness or chemoresistance. We discuss the emerging crosstalk between the UPR and related metabolic processes to ensure maintenance of protein homeostasis and its impact on cell transformation and tumor growth.Signifi cance: ER stress signaling is dysregulated in many forms of cancer and contributes to tumor growth as a survival factor, in addition to modulating other disease-associated processes, including cell migration, cell transformation, and angiogenesis. Evidence for targeting the ER stress signaling pathway as an anticancer strategy is compelling, and novel agents that selectively inhibit the UPR have demonstrated preliminary evidence of preclinical effi cacy with an acceptable safety profi le. Cancer Discov; 5(6);

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The FOXO Transcription Factor DAF-16 Bypasses ire-1 Requirement to Promote Endoplasmic Reticulum Homeostasis

Cited by 30 publications

References 44 publications

The genetics of isoflurane-induced developmental neurotoxicity

The genetics of isoflurane-induced developmental neurotoxicity

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

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