Akt1 signalling supports acinar proliferation and limits acinar‐to‐ductal metaplasia formation upon induction of acute pancreatitis (original) (raw)
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AKT1 regulates endoplasmic reticula stress and mediates adaptive response of pancreatic β-cells
Molecular and Cellular Biology, 2020
Isoforms of protein kinase B (also known as AKT) play important roles in mediating insulin and growth factor signals. Previous studies have suggested that the AKT2 isoform is critical for insulin regulated glucose metabolism while the role of the AKT1 isoform remains less clear. This study focuses on the effects of AKT1 on the adaptive response of pancreatic β-cells. Using a mouse model with inducible β-cell specific deletion of Akt1 gene (βA1KO mice), we showed that AKT1 is involved in high fat diet (HFD) induced growth and survival of β-cells but is unnecessary for them to maintain a population in the absence of metabolic stress. When unchallenged, βA1KO mice presented the same metabolic profile and β-cell phenotype as the control mice with intact Akt1 genes. When metabolic stress was induced by HFD, β-cells in control mice with intact Akt1 proliferated as a compensatory mechanism for metabolic overload. Similar effects were not observed in βA1KO mice. We further demonstrated that...
Frequent activation of AKT2 kinase in human pancreatic carcinomas
Journal of Cellular Biochemistry, 2002
Activation of AKT/protein kinase B promotes a variety of biological activities important in tumorigenesis, such as cell survival and cell cycle progression. We previously demonstrated amplification and overexpression of the AKT2 gene in a subset of human pancreatic carcinomas. In this investigation, we assessed AKT2 catalytic activity in 50 frozen pancreatic tissues (37 carcinomas, four benign tumors and nine normal pancreata) by in vitro kinase assay. Twelve of 37 (32%) pancreatic carcinomas showed markedly elevated levels of AKT2 activity compared to normal pancreata and begin pancreatic tumors. To delineate mechanisms contributing to AKT2 activation in malignant pancreatic tumors, we examined the status of upstream components of the phosphatilydlinositol 3-kinase (PI3K)/AKT pathway. Western blot analysis revealed loss of PTEN protein expression in two of the 12 pancreatic carcinomas with activated AKT2. In vitro PI3K assays demonstrated high levels of PI3K activity in seven carcinoma specimens that showed AKT2 activation. Immunohistochemical staining confirmed high levels of phosphorylated (active) AKT in malignant pancreatic tumors compared to normal pancreata. Overall, these data suggest that upstream perturbations of the PI3K/AKT pathway contribute to frequent activation of AKT2 in pancreatic cancer, which may contribute to the pathogenesis of this highly aggressive form of human malignancy.
American Journal of Physiology-Cell Physiology, 2000
Cytokines produced by pancreatic acinar cells may mediate cell death and recruitment of inflammatory cells into pancreas in pancreatitis and other disorders. Here, we demonstrate mRNA expression for a number of cytokines in acini isolated from rat pancreas. Using RNA from microscopically selected individual cells, we confirmed the acinar cell as a source for cytokine expression. Competitive RT-PCR, Western blot analysis, and immunocytochemistry showed large amounts of monocyte chemotactic protein-1 and interleukin-6 compared with other cytokines. Cytokine expression was inhibited by either inhibitors of p38 mitogen-activated protein kinase (MAPK), SB-202190 and SB-203580, or (less strongly) by the transcription factor nuclear factor (NF)-κB inhibitor MG-132. A combination of SB-203580 and MG-132 inhibited mRNA expression of all cytokines by >90%. The results suggest a major role for p38 MAPK and involvement of NF-κB in cytokine expression in pancreatic acinar cells. In contrast t...
The PI3K/Akt Pathway in Meta-Inflammation
International Journal of Molecular Sciences
Obesity is a global epidemic representing a serious public health burden as it is a major risk factor for the development of cardiovascular disease, stroke and all-cause mortality. Chronic low-grade systemic inflammation, also known as meta-inflammation, is thought to underly obesity’s negative health consequences, which include insulin resistance and the development of type 2 diabetes. Meta-inflammation is characterized by the accumulation of immune cells in adipose tissue, a deregulation in the synthesis and release of adipokines and a pronounced increase in the production of proinflammatory factors. In this state, the infiltration of macrophages and their metabolic activation contributes to complex paracrine and autocrine signaling, which sustains a proinflammatory microenvironment. A key signaling pathway mediating the response of macrophages and adipocytes to a microenvironment of excessive nutrients is the phosphoinositide 3-kinase (PI3K)/Akt pathway. This multifaceted network...