Basic—Liver, Pancreas, and Biliary TractRegulator of Calcineurin 1 Controls Growth Plasticity of Adult Pancreas
Section snippets
Materials
The PI camostat was provided by Ono Pharmaceuticals (Osaka, Japan). TaqMan reverse transcription and Expand polymerase chain reaction (PCR) kits were purchased from Roche (Basel, Switzerland). Antibodies and all other reagents are listed in Supplementary Materials and Methods.
Animals and Treatment
Animal experiments, including PI feeding and FK506 injections, are outlined in Supplementary Materials and Methods or performed as previously described.8 To overexpress Rcan1 in pancreatic acini, we bred FLAG-Rcan1 (Rcan1)
RNA Microarray Analysis of PI-Induced and CN-Dependent Genes
We performed genome-wide expression profiling of the 2-hour time point of CCK-driven pancreatic growth, focused on CN-dependent genes in particular. Pancreatic RNA was harvested from mice fasted overnight or fasted and refed PI-containing chow for 2 hours and injected with either 3 mg/kg of FK506 or vehicle then hybridized with Affymetrix 430A genechips (4 mice/group, 16 chips total), as outlined in Figure 1A, top. PI feeding led to a significant (>3-fold, q ≤ 0.08) increase in expression of 81
Discussion
Physiologic growth of the pancreas takes place in response to high protein diet, hyperphagia, pregnancy, and lactation.20 The molecular mechanisms that govern this adaptive response, however, are poorly understood. Here, we examined the expression profile of CCK-mediated pancreatic growth. We focused on CN-NFAT signaling axis, identifying several novel growth-related, NFAT-regulated genes. We also demonstrate that 1 of these genes, Rcan1, functions as a CN/NFAT-dependent feedback inhibitor that
Acknowledgments
The authors thank Linda Samuelson (University of Michigan) for CCK-deficient mice, Bradley Nelson for help with immunohistochemistry, and Scott Tomlins and the Arul Chinnayian laboratory (University of Michigan) for assistance with bioinformatics.
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RCAN1 is a marker of oxidative stress, induced in acute pancreatitis
2018, PancreatologyCitation Excerpt :It has been shown to be regulated in neuronal cells by both CN-NFAT signaling, NFκB [28] and oxidative stress [29]. The specific role of Rcan1 in the pancreas is not as well studied, however overexpression of Rcan1 in pancreatic β-cells has been shown to cause hypoinsulinemia, β-cell dysfunction and diabetes [30] and CN-NFAT signaling induced Rcan1 expression in acinar cells, following damage-induced regeneration [15]. One of the most commonly used in vivo models of AP is the caerulein induction model [31], where hyper-stimulation with caerulein induces zymogen activation [32], ROS production and AP [33,34].
NFATc1 links EGFR signaling to induction of sox9 transcription and acinar-ductal transdifferentiation in the pancreas
2015, GastroenterologyCitation Excerpt :The identification of Cox2 as an EGFR/NFAT target already points toward critical functions of the EGFR/NFAT cascade for the integration of inflammatory signals during carcinogenesis. In particular, during pancreatic cancer formation, NFAT proteins have been shown to play a central role in the integration of environmental signals into oncogenic transcriptional processes that mediate proliferation, cellular differentiation, and adaptation to inflammation.21,22,28,30 In this study, we showed that sustained pancreatic inflammation induced a strong up-regulation of NFATc1 in metaplastic areas of both murine and human chronic pancreatitis models.
Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin
2013, Journal of Biological ChemistryCitation Excerpt :Each of the inhibitors reduced the activation of our reporter system driven by the NFAT promoter, suggesting that TLCS injury is mediated by calcineurin. Further, infecting cells with an adenovirus that overexpresses an endogenous inhibitor of calcineurin, Mcip1, also known as regulator of calcineurin 1 (Rcan1) (33), showed similar results (Fig. 1F). We demonstrate that TLCS promotes transcriptional activation via a calcineurin-specific pathway.
Evaluating the mode of action of perfluorooctanoic acid-induced liver tumors in male Sprague-Dawley rats using a toxicogenomic approach
2024, Journal of Environmental Science and Health, Part C: Toxicology and CarcinogenesisRegulation of Pancreatic Protein Synthesis and Growth
2023, The Pancreas: an Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition
Conflicts of interest The authors disclose no conflicts.
Funding Supported by NIH grants DK 59578 (to J.A.W.) and P30 DK-34933 (Michigan Gastrointestinal Peptide Center); by Systems and Integrative Biology Training Grant (T32 GM008322; to G.T.G.) and the Medical Scientist Training Program (G.T.G.); by DK52067 (to C.D.L.), R21 DK068414 (to B.J.), DK-0077423 (to S.J.C.), and HL072016 (B.A.R.); and for use of the Morphology and Image Analysis Core of the Michigan Diabetes Research and Training Center funded by NIH5P60 DK20572.