Knocking out the door to tunicamycin entry

Bassik, Michael C.; Kampmann, Martin

doi:10.1073/pnas.1109035108

Cited by 32 publications

(21 citation statements)

References 14 publications

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“…In order to reproducibly generate ER stress in the liver, mice were administered tunicamycin, a nucleoside antibiotic that inhibits the first step in glycoprotein synthesis, leading to generation of ER stress [20]. To assess the effectiveness of the antibiotic in generating ER stress in the liver in vivo, eIF2α phosphorylation on Ser51 was assessed by Western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we assessed the effect of ER stress on REDD1 expression in the liver by treating mice with a well-characterized initiator of ER stress, tunicamycin [20]. We show that tunicamycin treatment generates ER stress in the liver as assessed by enhanced phosphorylation of the α-subunit of eIF2 and enhanced splicing of the mRNA encoding XBP1, concomitant with induction of REDD1 mRNA expression.…”

Section: Introductionmentioning

confidence: 99%

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Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2α phosphorylation, ATF4-dependent cascade

Kimball

Jefferson

2012

Biochemical and Biophysical Research Communications

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Since the endoplasmic reticulum (ER) plays a vital role in hepatocyte function, it is not surprising that a variety of liver-related diseases are associated with ER stress. As in other tissues, ER stress in the liver leads to generation of the unfolded-protein response resulting in activation of a transcriptional program that promotes restoration of homeostasis within the lumen of the ER. Previous studies using cells in culture demonstrated that ER stress induces expression of REDD1 (regulated in development and DNA damage responses), a potent repressor of signaling through the protein kinase referred to as the mechanistic target of rapamycin in complex 1 (mTORC1). In the present study, the results from the cell culture experiments were extended to show that tunicamycin-mediated ER stress in the liver in vivo also induces REDD1 gene expression. Moreover, the induction of REDD1 gene expression was shown to require the protein kinase PERK and enhanced phosphorylation of its substrate, the α-subunit of eukaryotic initiation factor 2.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2α phosphorylation, ATF4-dependent cascade

Kimball

Jefferson

2012

Biochemical and Biophysical Research Communications

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“…Among chemical ER stressors, tunicamycin (TUN), a naturally occurring antibiotic, induces ER stress by inhibiting N-linked protein glycosylation (Bassik and Kampmann, 2011). ER stress can also be induced by the transition metal cadmium (Cd 2+ ) via generation of reactive oxygen species (Kitamura and Hiramatsu, 2010).…”

mentioning

confidence: 99%

Rapamycin: A therapy of choice for endoplasmic reticulum stress-induced renal proximal tubule toxicity?

2015

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“…Tm causes ER stress and subsequent steatosis by blocking the activity of DPAGT1, thereby inhibiting N-linked protein glycosylation and causing accumulation of hypoglycosylated and unfoldable proteins in the ER. 38,39 The UPR is significantly upregulated after both treatments 28,30,43 and ER stress is observed in patients with NAFLD and ALD. 58,68 Interestingly, the inability to detect DBP-GFP fluorescence in Tm-treated fish may reflect the propensity of EGFP to aggregate in the oxidizing environment in the ER 79 which is further enhanced under conditions that affect ER redox balance.…”

Section: Discussionmentioning

confidence: 99%

“…Tm blocks Nlinked glycosylation of proteins by inhibition of DPAGT1, 38,39 causing ER stress and, by an as of yet unknown mechanism, results in fatty liver disease in mammals [40][41][42] and zebrafish. 43,44 To determine the effect of EtOH and Tm on liver morphology, we employed a transgenic zebrafish line expressing dsRed specifically in hepatocytes (Tg(fabp10:dsRed)).…”

Section: Zebrafish Larvae Exposed To Tunicamycin or Ethanol Develop Fmentioning

confidence: 99%

Defining Hepatic Dysfunction Parameters in Two Models of Fatty Liver Disease in Zebrafish Larvae

et al. 2013

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Fatty liver disease in humans can progress from steatosis to hepatocellular injury, fibrosis, cirrhosis, and liver failure. We developed a series of straightforward assays to determine whether zebrafish larvae with either tunicamycin-or ethanol-induced steatosis develop hepatic dysfunction. We found altered expression of genes involved in acute phase response and hepatic function, and impaired hepatocyte secretion and disruption of canaliculi in both models, but glycogen deficiency in hepatocytes and dilation of hepatic vasculature occurred only in ethanol-treated larvae. Hepatic stellate cells (HSCs) become activated during liver injury and HSC numbers increased in both models. Whether the excess lipids in hepatocytes are a direct cause of hepatocyte dysfunction in fatty liver disease has not been defined. We prevented ethanol-induced steatosis by blocking activation of the sterol response element binding proteins (Srebps) using gonzo mbtps1 mutants and scap morphants and found that hepatocyte dysfunction persisted even in the absence of lipid accumulation. This suggests that lipotoxicity is not the primary cause of hepatic injury in these models of fatty liver disease. This study provides a panel of parameters to assess liver disease that can be easily applied to zebrafish mutants, transgenics, and for drug screening in which liver function is an important consideration.

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Knocking out the door to tunicamycin entry

Cited by 32 publications

References 14 publications

Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2α phosphorylation, ATF4-dependent cascade

Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2α phosphorylation, ATF4-dependent cascade

Rapamycin: A therapy of choice for endoplasmic reticulum stress-induced renal proximal tubule toxicity?

Defining Hepatic Dysfunction Parameters in Two Models of Fatty Liver Disease in Zebrafish Larvae

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