Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias (T-ALL), making this receptor a promising target for drugs such as γ-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates PTEN expression and the activity of the PI3K-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with resistance to NOTCH1 inhibition in human T-ALL. Overall, these findings identify the transcriptional control of PTEN and the regulation of the PI3K/ AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.NOTCH receptors directly transduce extracellular signals at the cell surface into changes in gene expression that regulate differentiation, self renewal, proliferation and apoptosis 1 . Constitutively active forms of the NOTCH1 receptor contribute to over 50% of human T-cell lymphoblastic leukemias and lymphomas (T-ALL) 2 , and have also been implicated in the pathogenesis of solid tumors, such as breast carcinomas, gliomas and neuroblastoma 3-5 . #Adolfo A. Ferrando (af2196@columbia.edu) and Maria Dominguez (m.dominguez@umh.es) are co-senior corresponding authors.
We have proposed the "glucolipotoxicity" hypothesis in which elevated free fatty acids (FFAs) together with hyperglycemia are synergistic in causing islet beta-cell damage because high glucose inhibits fat oxidation and consequently lipid detoxification. The effects of 1-2 d culture of both rat INS 832/13 cells and human islet beta-cells were investigated in medium containing glucose (5, 11, 20 mM) in the presence or absence of various FFAs. A marked synergistic effect of elevated concentrations of glucose and saturated FFA (palmitate and stearate) on inducing beta-cell death by apoptosis was found in both INS 832/13 and human islet beta-cells. In comparison, linoleate (polyunsaturated) synergized only modestly with high glucose, whereas oleate (monounsaturated) was not toxic. Treating cells with the acyl-coenzyme A synthase inhibitor triacsin C, or the AMP kinase activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside that redirect lipid partitioning to oxidation, curtailed glucolipotoxicity. In contrast, the fat oxidation inhibitor etomoxir, like glucose, markedly enhanced palmitate-induced cell death. The data indicate that FFAs must be metabolized to long chain fatty acyl-CoA to exert toxicity, the effect of which can be reduced by activating fatty acid oxidation. The results support the glucolipotoxicity hypothesis of beta-cell failure proposing that elevated FFAs are particularly toxic in the context of hyperglycemia.
Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced -cell apoptosis. First, ATF3 is induced in  cells by signals relevant to -cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-B and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in  cells develop abnormal islets and defects secondary to -cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine-or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced -cell apoptosis.It is widely accepted that autoimmunity is the main cause of type 1 but not type 2 diabetes. Despite this difference, -cell death plays an important role in the pathophysiological progression of both diseases (15,43,45). On one hand, proinflammatory cytokines (interleukin-1 , tumor necrosis factor alpha [TNF-␣], and gamma interferon [IFN-␥]) destroy  cells in the islets of Langerhans, leading to the pathogenesis of type 1 diabetes (11,14,15,42); on the other hand, elevated glucose and free fatty acids (FFAs)-common metabolic abnormalities in type 2 diabetes-induce -cell death, contributing to the progression of the disease (13,32,35,53,62). Emerging evidence indicates that activation of the NF-B and Jun N-terminal kinase/stress-activated protein kinase (JNK/ SAPK) signaling pathways is a key event leading to cell death, when  cells are exposed to these signals: proinflammatory cytokines, elevated glucose, and elevated FFAs (12,15,16,43,49). Furthermore, activation of these pathways has been demonstrated to impair insulin signaling (1,17,18,36) and play a role in type 2 diabetes (63,71). Therefore, these stress-activated signaling pathways constitute a common molecular mechanism in the pathophysiological progression of type 1 and type 2 diabetes.Thus far, inducible nitric oxide (NO) synthase (iNOS), whose expression leads to NO production, is one of the best known target genes for these pathways (14-16, 42, 54). Several lines of evidence indicate that iNOS plays an important role in the pathogenesis of diabetes. (i) iNOS is induced in the islets by cytokines (16) and is expressed in the islets of diabetes prone BB rats (33) and nonobese diabetic (NOD) mice (55,58). (ii) Transgenic mice expressing iNOS in  cells develop -cell destruction and diabetes (60). (iii)  cells lacking functional iNOS are partially protected ...
Glucagon-like peptide-1-(7±36)amide (GLP-1) is secreted by the enteroendocrine L-cells in response to fat meals and carbohydrates [1,2]. It is a potent glucoincretin hormone which acts as a competence factor in determining the ability of the beta-cell to respond to glucose by secretion of insulin [3], K/ATP channels closure [4] and the induction of immediate early response genes (IEG) [5]. It is a potentially important drug in the treatment of diabetes particularly Diabetologia (1999) AbstractAims/hypothesis. Glucagon-like peptide-1 is a potent glucoincretin hormone and a potentially important drug in the treatment of Type II (non-insulin-dependent) diabetes mellitus. We have investigated whether it acts as a growth factor in beta (INS-1)-cells and have studied the signalling pathways and transcription factors implicated in this process. Methods. Cell proliferation was assessed by tritiated thymidine incorporation measurements. We have examined the action of glucagon-like peptide-1 on the enzymatic activity of phosphatidylinositol 3-kinase. The DNA binding activity of transcription factors was investigated by electrophoretic mobility shift assay. Measurements of mRNA were done using the northern technique. Results. Glucagon-like peptide-1 caused an increase in tritiated thymidine incorporation in beta (INS-1)-cells and phosphatidylinositol 3-kinase activity in a dose-dependent manner non-additively with glucose. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294 002 blocked the effects of glucagon-like peptide-1 on DNA synthesis. Transcription factor pancreatic and duodenal homebox gene 1 (PDX-1) DNA binding activity was increased by glucagon-like peptide-1 at 3 or 11 mmol/l glucose and the phosphatidylinositol 3-kinase inhibitor LY294 002 suppressed the action of glucagon-like peptide-1 on PDX-1 DNA binding activity. Glucagon-like peptide-1 and glucose alone did not change activating protein-1 DNA binding activity. They synergised, however, to increase the activity of activating protein-1. Glucagon-like peptide-1 also increased the expression of PDX-1, glucose transporter 2, glucokinase and insulin mRNAs. Finally, glucagon-like peptide-1 increased the incorporation of tritiated thymidine in isolated rat islets. Conclusion/interpretation. The results suggest that glucagon-like peptide-1 may act as a growth factor for the beta cell by a phosphatidylinositol 3-kinase mediated event. Glucagon-like peptide-1 could also regulate the expression of the insulin gene and genes encoding enzymes implicated in glucose transport and metabolism through the phosphatidylinositol 3-kinase/PDX-1 transduction signalling pathway. [Diabetologia (1999) 42: 856±864]
We previously provided evidence that glucagon-like peptide 1 (GLP-1) induces pancreatic -cell growth nonadditively with glucose in a phosphatidylinositol (PI) 3-kinase-and protein kinase C -dependent manner. However, the exact mechanism by which the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor (GPCR) superfamily, activates the PI 3-kinase signaling pathway to promote -cell growth remains unknown. We hypothesized that the GLP-1R could activate PI 3-kinase and promote -cell proliferation through transactivation of the epidermal growth factor (EGF) receptor (
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