The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in <i>Ins2</i><sup>+/Akita</sup> pancreatic β cells

Nozaki, Junichi; Kubota, Hiroshi; Yoshida, Hiderou; Naitoh, Motoko; Goji, Junko; Yoshinaga, Takao; Mori, Kazutoshi; Koizumi, Akio; Nagata, Kazuhiro

doi:10.1111/j.1356-9597.2004.00721.x

Cited by 116 publications

(131 citation statements)

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“…Further support for a role of ER stress in diabetes was presented in mice with genetic ablation of PERK or the chaperone P58 IPK that resulted in islet beta cell death and hyperglycaemia [35,36]. Moreover, a recent study has shown that in the Akita mouse model of diabetes, a mutation in Ins2 resulted in misfolding of the insulin protein causing ER stress and beta cell apoptosis [37]. Chronic exposure of islets and beta cells to fatty acids is known to cause dysfunction and cellular death [38], and this apoptosis has recently been shown to be the result of activation of an ER stress response [39][40][41].…”

Section: Possible Mechanisms That Could Explain Hypersecretion-inducementioning

confidence: 98%

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

et al. 2008

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Section: Possible Mechanisms That Could Explain Hypersecretion-inducementioning

confidence: 98%

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

et al. 2008

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“…Mouse pancreatic β cell lines carrying the Ins2 +/+ and Ins2 +/Akita genes were cultured as described previously (Nozaki et al, 2004). HeLa, mouse L929, NIH 3T3, and BALB/c 3T3 cells were cultured in Dulbecco's modified essential medium supplemented with 10% fetal bovine serum.…”

Section: Cell Culturementioning

confidence: 99%

“…The ERSE-II sequence on the ARMET promoter was disrupted by site-directed mutagenesis. The effector construct containing mouse wild-type Ins2 and its C96Y mutant was described previously (Nozaki et al, 2004). The reporter gene constructs driven by the human wild-type and ERSE-disrupted GRP78 promoters were described previously (Yoshida et al, 1998).…”

Section: Construction Of Plasmidsmentioning

confidence: 99%

“…Since Cys96 is essential for a disulfide bond in insulin, proinsulin carrying this mutation becomes structurally unstable and is prone to aggregation (Ron, 2002) due to an exposed hydrophobic surface (Yoshinaga et al, 2005). Previously, we established β cell lines from Ins2 +/Akita mice and reported that ER chaperones and the ATF6 and XBP1 transcription factors are more strongly activated in Ins2 +/Akita cells than in Ins2 +/+ cells (Nozaki et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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ARMET is a Soluble ER Protein Induced by the Unfolded Protein Response via ERSE-II Element

Mizobuchi

Hoseki

Kubota

et al. 2007

Cell Struct. Funct.

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These two authors equally contributed to this work.ABSTRACT. Arginine rich, mutated in early stage of tumors (ARMET) was first identified as a human gene highly mutated in a variety of cancers. However, little is known about the characteristics of the ARMET protein and its expression. We identified ARMET as a gene upregulated by endoplasmic reticulum (ER) stress. Here, we show that the mouse homologue of ARMET is an 18-kDa soluble ER protein that is mature after cleavage of a signal sequence and has four intramolecular disulfide bonds, including two in CXXC sequences. ER stress stimulated ARMET expression, and the expression patterns of ARMET mRNA and protein in mouse tissues were similar to those of Grp78, an Hsp70-family protein required for quality control of proteins in the ER. A reporter gene assay using a mouse ARMET promoter revealed that the unfolded protein response of the ARMET gene is regulated by an ERSE-II element whose sequence is identical to that of the HERP gene. ARMET is the second fully characterized ERSE-II-dependent gene and likely contributes to quality control of proteins in the ER.

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“…Importantly, in the Akita mouse, diabetes resulted purely as a consequence of insulin misfolding leading to ER stress in the absence of any defect of insulin production or sensitivity, showing that ER stress can play a causal role in diabetes development. Cell lines established from ␤-cells of these mice exhibited continuous activation of the master regulators of the ER stress response, ATF6 and XBP1 (24). Examination of postmortem sections of pancreata from normal compared with type 2 diabetic subjects showed up-regulation of ER stress markers, including BiP, DnaJC3 (p58 IPK ), and CHOP in the pancreata from diabetic subjects (23).…”

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confidence: 99%

Hepatic Nuclear Factor 1α (HNF1α) Dysfunction Down-regulates X-box-binding Protein 1 (XBP1) and Sensitizes β-Cells to Endoplasmic Reticulum Stress

Kirkpatrick

Wiederkehr

Baquié

et al. 2011

Journal of Biological Chemistry

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Correct endoplasmic reticulum (ER) function is critical for the health of secretory cells, such as the pancreatic ␤-cell, and ER stress is often a contributory factor to ␤-cell death in type 2 diabetes. We have used an insulin-secreting cell line with inducible expression of dominant negative (DN) HNF1␣, a transcription factor vital for correct ␤-cell development and function, to show that HNF1␣ is required for Xbp1 transcription and maintenance of the normal ER stress response. DN HNF1␣ expression sensitizes the ␤-cell to ER stress by directly downregulating Xbp1 transcription, whereas Atf6 is unaffected. Furthermore, DN HNF1␣ alters calcium homeostasis, resulting in elevated cytoplasmic calcium and increased store-operated calcium entry, whereas mitochondrial calcium uptake is normal. Loss of function of XBP1 is toxic to the ␤-cell and decreases production of the ER chaperone BiP, even in the absence of ER stress. DN HNF1␣-induced sensitivity to cyclopiazonic acid can be partially rescued with the chemical chaperone tauroursodeoxycholate. Rat insulin 2 promoter-DN HNF1␣ mouse islets express lower levels of BiP mRNA, synthesize less insulin, and are sensitized to ER stress relative to matched control mouse islets, suggesting that this mechanism is also operating in vivo. Maturity onset diabetes of the young 3 (MODY3)2 is caused by heterozygous mutations in the transcription factor Hnf1␣ (1), which lead to a primary defect in ␤-cell function without insulin resistance. Almost 200 MODY3 mutations in Hnf1␣ have been characterized, with missense mutations occurring most frequently, whereas the appearance of frameshift or nonsense mutations is also observed. MODY3 mutations often act through haploinsufficiency (2), but they can also act through a dominant negative mechanism, as is the case for the (frequently occurring) frameshift mutation P291 fsinsC (3, 4). HNF1␣ was originally discovered as a regulator of hepatic gene expression but has since been found to be expressed in the pancreas (5) and involved in transcription of ␤-cell-specific genes (6, 7). However, genome-wide studies have also demonstrated that its effects on gene expression in the liver and pancreatic islet are strikingly different (8). To characterize the role of HNF1␣ in ␤-cells, a dominant negative (DN) mutant has been used, which carries a substitution of 83 amino acids in its DNA-binding domain, whereas its dimerization domain remains intact (Fig. 1A). This artificial DN mutant forms non-functional dimers with the endogenous protein, preventing it from activating its target genes (9). This has led to the discovery that in insulinsecreting INS-1 cells, suppression of HNF1␣ activity following induction of the DN gene impairs metabolism-secretion coupling (7, 10) and reduces insulin secretion in response to glucose, as well as reducing transcription of the insulin I gene (11). Expression of the transgene also leads to apoptosis in these cells after 48 h of induction (12).During insulin biosynthesis, the nascent chain is translocated into the endop...

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The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2^+/Akita pancreatic β cells

Abstract: The dominant C96Y mutation of one of the two murine insulin genes, Ins2 , causes diabetes mellitus in 'Akita' mice. Here we established pancreatic islet β β β β cell lines from heterozygous mice ( Ins2

Cited by 116 publications

References 44 publications

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

ARMET is a Soluble ER Protein Induced by the Unfolded Protein Response via ERSE-II Element

Hepatic Nuclear Factor 1α (HNF1α) Dysfunction Down-regulates X-box-binding Protein 1 (XBP1) and Sensitizes β-Cells to Endoplasmic Reticulum Stress

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The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2+/Akita pancreatic β cells

Abstract: The dominant C96Y mutation of one of the two murine insulin genes, Ins2 , causes diabetes mellitus in 'Akita' mice. Here we established pancreatic islet β β β β cell lines from heterozygous mice ( Ins2

Cited by 116 publications

References 44 publications

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

ARMET is a Soluble ER Protein Induced by the Unfolded Protein Response via ERSE-II Element

Hepatic Nuclear Factor 1α (HNF1α) Dysfunction Down-regulates X-box-binding Protein 1 (XBP1) and Sensitizes β-Cells to Endoplasmic Reticulum Stress

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The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2^+/Akita pancreatic β cells