Inhibitor of differentiation proteins protect against oxidative stress by regulating the antioxidant–mitochondrial response in mouse beta cells

Bensellam, Mohammed; Montgomery, Magdalene K; Luzuriaga, Jude; Chan, Jeng Yie; Laybutt, D. Ross

doi:10.1007/s00125-015-3503-1

Cited by 39 publications

(29 citation statements)

References 50 publications

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“…Moreover Bmp2 and Id1 expression is also increased by free fatty acids [107,108]. These observations are also reflected in increased expression of BMP2/4 and ID1 in islets from type 2 diabetic mice [90,99,109].…”

Section: Bmp2 Expression Has Been Found To Be Upregulated By Inflammamentioning

confidence: 94%

“…Likewise, the SMAD proteins and targets like the Id-proteins are expressed [97][98][99]. Thus, the entire BMP signalling machinery is present in pancreatic islets.…”

Section: Expression and Regulation Of Bmp Signalling In Adulthood/diamentioning

confidence: 98%

“…Inflammatory cytokines and BMP2/4 stimulation of primary pancreatic islets induce the expression of Id1-4 [90,107]. Id1 expression is also increased in islets from type 2 diabetic mice [99]. The Id proteins have been shown to bind to the bHLH protein NeuroD, which is essential for maintaining beta-cell maturity and function [92].…”

Section: Effect Of Bmps On Glucose Homeostasis and Pancreatic Islet Fmentioning

confidence: 99%

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Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism

Grgurević

Christensen

Schulz

et al. 2016

Cytokine & Growth Factor Reviews

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Section: Bmp2 Expression Has Been Found To Be Upregulated By Inflammamentioning

confidence: 94%

“…Likewise, the SMAD proteins and targets like the Id-proteins are expressed [97][98][99]. Thus, the entire BMP signalling machinery is present in pancreatic islets.…”

Section: Expression and Regulation Of Bmp Signalling In Adulthood/diamentioning

confidence: 98%

Section: Effect Of Bmps On Glucose Homeostasis and Pancreatic Islet Fmentioning

confidence: 99%

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Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism

Grgurević

Christensen

Schulz

et al. 2016

Cytokine & Growth Factor Reviews

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“…Protein analysis Western blotting and immunostaining were performed as previously described [7,20]. Western blot bands were quantified by densitometry and normalised to total protein or loading control (actin, tubulin or 14-3-3).…”

Section: Methodsmentioning

confidence: 99%

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

et al. 2016

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Aims/hypothesis Hypoxia may contribute to beta cell failure in type 2 diabetes and islet transplantation. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum (ER) homeostasis. Here we investigated whether or not hypoxia regulates the UPR in beta cells and the role the adaptive UPR plays during hypoxic stress. Methods Mouse islets and MIN6 cells were exposed to various oxygen (O 2 ) tensions. DNA-damage inducible transcript 3 (DDIT3), hypoxia-inducible transcription factor (HIF)1α and HSPA5 were knocked down using small interfering (si)RNA; Hspa5 was also overexpressed. db/db mice were used. Results Hypoxia-response genes were upregulated in vivo in the islets of diabetic, but not prediabetic, db/db mice. In isolated mouse islets and MIN6 cells, O 2 deprivation (1-5% vs 20%; 4-24 h) markedly reduced the expression of adaptive UPR genes, including Hspa5, Hsp90b1, Fkbp11 and spliced Xbp1. Coatomer protein complex genes (Copa, Cope, Copg [also known as Copg1], Copz1 and Copz2) and ER-to-Golgi protein trafficking were also reduced, whereas apoptotic genes (Ddit3, Atf3 and Trb3 [also known as Trib3]), c-Jun N-terminal kinase (JNK) phosphorylation and cell death were increased. Inhibition of JNK, but not HIF1α, restored adaptive UPR gene expression and ER-to-Golgi protein trafficking while protecting against apoptotic genes and cell death following hypoxia. DDIT3 knockdown delayed the loss of the adaptive UPR and partially protected against hypoxia-induced cell death. The latter response was prevented by HSPA5 knockdown. Finally, Hspa5 overexpression significantly protected against hypoxia-induced cell death. Conclusions/interpretation Hypoxia inhibits the adaptive UPR in beta cells via JNK and DDIT3 activation, but independently of HIF1α. Downregulation of the adaptive UPR contributes to reduced ER-to-Golgi protein trafficking and increased beta cell death during hypoxic stress.

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“…Expression of other antioxidant response genes was also increased (e.g. Srxn1, G6pd, Prdx4 ) (Bensellam et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

Molecular Changes in the Nasal Cavity after N, N-dimethyl-p-toluidine Exposure

et al. 2016

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N,N-Dimethyl-p-toluidine (DMPT) (Cas No. 99-97-8), an accelerant for methyl methacrylate monomers in medical devices, is a nasal cavity carcinogen in a 2-year cancer study in male and female F344/N rats, with the nasal tumors arising from the transitional cell epithelium. In this study we exposed male F344/N rats for five days to DMPT (0, 1, 6, 20, 60 or 120 mg/kg (oral gavage)) to explore early changes in the nasal cavity after short-term exposure. Lesions occurred in the nasal cavity including hyperplasia of transitional cell epithelium (60 and 120 mg/kg). Nasal tissue was rapidly removed and preserved for subsequent laser capture microdissection and isolation of the transitional cell epithelium (0 and 120 mg/kg) for transcriptomic studies. DMPT transitional cell epithelium gene transcript patterns were characteristic of an anti-oxidative damage response (e.g. Akr7a3, Maff, Mgst3), cell proliferation, and decrease in signals for apoptosis. Amino acid transporters transcripts were upregulated (e. g, Slc7a11). The DMPT nasal transcript expression pattern was similar to that found in the rat nasal cavity after formaldehyde exposure with over 1000 transcripts in common. Molecular changes in the nasal cavity after DMPT exposure suggest that oxidative damage is a mechanism for the DMPT toxic and/or carcinogenic effects.

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Inhibitor of differentiation proteins protect against oxidative stress by regulating the antioxidant–mitochondrial response in mouse beta cells

Cited by 39 publications

References 50 publications

Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism

Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

Molecular Changes in the Nasal Cavity after N, N-dimethyl-p-toluidine Exposure

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