Interleukin‐1 induces rapid and transient expression of the c‐fos proto‐oncogene in isolated pancreatic islets and in purified β‐cells

Hughes, Jonathan H.; Watson, Mark A.; Easom, Richard A.; Turk, John; McDaniel, Michael L.

doi:10.1016/0014-5793(90)81499-e

Cited by 24 publications

(6 citation statements)

References 32 publications

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“…Previous studies have shown that FOS/JUN activation is involved in cytokine and mechanical stress-induced beta cell death (Abdelli et al, 2007; Hughes et al, 1990) and amylin-induced apoptosis (Zhang et al, 2002). Here, we found that CDKAL1 −/− mediated activation of the FOS/JUN pathway through fatty acids may be a further effector of FOS/JUN regulated beta cell survival, providing mechanistic insight into how CDKAL1 locus may contribute to diabetes progression.…”

Section: Discussionmentioning

confidence: 99%

An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery

et al. 2016

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SUMMARY Genome wide association studies (GWAS) have increased our knowledge of loci associated with a range of human diseases. However, applying such findings to elucidate pathophysiology and promote drug discovery remains challenging. Here, we created isogenic human embryonic stem cells (hESCs) with mutations in GWAS-identified susceptibility genes for type 2 diabetes. In pancreatic betalike cells differentiated from these lines, we found that mutations in CDKAL1, KCNQ1 and KCNJ11 led to impaired glucose secretion in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1 mutant insulin+ cells were also hypersensitive to glucolipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1 specific defects in vitro and in vivo by inhibiting the FOS/JUN pathway. Our approach of a proof-of-principle platform, which uses isogenic hESCs for functional evaluation of GWAS-identified loci and identification of a drug candidate that rescues gene-specific defects, paves the way for precision therapy of metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery

et al. 2016

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“…In this context, it is noteworthy that treatment of islet cells with cytokines (e.g. interleukin l-~) leads to a rise in cGMP [29] and an increase in c-fos expression [30,31]. The temporal relationship between these events requires further study but the possibility should not be excluded that cGMP may be central to the cytotoxic actions of cytokines in islet cells.…”

Section: Resultsmentioning

confidence: 99%

Evidence for the involvement of cGMP and protein kinase G in nitric oxide‐induced apoptosis in the pancreatic B‐cell line, HIT‐T15

et al. 1997

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Intracellular production of nitric oxide (NO) is thought to mediate the pancreatic B-cell-directed cytotoxicity of cytokines in insulin-dependent diabetes mellitus, and recent evidence has indicated that this may involve induction of apoptosis. A primary effect of NO is to activate soluble guanylyl cyclase leading to increased cGMP levels and this effect has been demonstrated in pancreatic B-cells, although no intracellular function has been defined for islet cGMP. Here we demonstrate that the NO donor, GSNO, induces apoptosis in the pancreatic B-celliine HIT-TI5 in a dose-and time-dependent manner. This response was significantly attenuated by micromolar concentrations of a specific inhibitor of soluble guanylyl cyclase, ODQ, and both 8-bromo cGMP (100 ~) and dibutyryl cGMP (300 ~) were able to fully relieve this inhibition. In addition, incubation of HIT -T15 cells with each cGMP analogue directly promoted cell death in the absence of ODQ. KT5823, a potent and highly selective inhibitor of cGMP-dependent protein kinase (PKG), abolished the induction of cell death in fiT cells in response to either GSNO or cGMP analogues. This effect was dose-dependent over the concentration range of 10--250 nM. Overall, these data provide evidence that the activation of apoptosis in HIT-TI5 cells by NO donors is secondary to a rise in cGMP and suggest that the pathway controlling cell death involves activation of PKG.

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“…It has been demonstrated that PKG can regulate gene expression, and among others, it activates c-fos, an early gene that is often expressed in cells undergoing apoptosis (35). Data showing that IL-1␤ induces expression of c-fos in rat islets and in purified rat ␤-cells (36,37) favor this suggestion.…”

Section: Discussionmentioning

confidence: 95%

Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis.

et al. 2001

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Interleukin‐1 induces rapid and transient expression of the c‐fos proto‐oncogene in isolated pancreatic islets and in purified β‐cells

Cited by 24 publications

References 32 publications

An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery

An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery

Evidence for the involvement of cGMP and protein kinase G in nitric oxide‐induced apoptosis in the pancreatic B‐cell line, HIT‐T15

Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis.

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