{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Gurda GT"],"funding":["NIDDK NIH HHS","NHLBI NIH HHS","NIGMS NIH HHS"],"pagination":["609-19, 619.e1-6"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC2929702"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["139(2)"],"pubmed_abstract":["Growth of exocrine pancreas is regulated by gastrointestinal hormones, notably cholecystokinin (CCK). CCK-driven pancreatic growth requires calcineurin (CN), which activates Nuclear Factor of Activated T cells (NFATs), but the genetic underpinnings and feedback mechanisms that regulate this response are not known.Pancreatic growth was stimulated by protease inhibitor (PI)-containing chow, which induces secretion of endogenous CCK. Expression profiling of PI stimulation was performed on Affymetrix 430A chips, and CN was inhibited via FK506. Exocrine pancreas-specific overexpression of CN inhibitor Regulator of Calcineurin 1 (Rcan1) was achieved by breeding elastase-Cre(estrogen receptor [ER]) transgenics with \"flox-on\" Rcan1 mice.CN inhibitor FK506 blocked expression of 38 genes, as confirmed by quantitative polymerase chain reaction. The CN-dependent genes were linked to growth-related processes, whereas their promoters were enriched in NFAT and NFAT/AP1 sites. Multiple NFAT targets, including Rcan1, Rgs2, HB-EGF, Lif, and Gem, were validated by chromatin immunoprecipitation. One of these, a CN feedback inhibitor Rcan1, was induced >50 fold during 1-8 hours course of pancreatic growth and strongly inhibited (>99%) by FK506. To examine its role in pancreatic growth, we overexpressed Rcan1 in an inducible, acinar-specific fashion. Rcan1 overexpression inhibited CN-NFAT signaling, as shown using an NFAT-luciferase reporter and quantitative polymerase chain reaction. Most importantly, the increase in exocrine pancreas size, protein/DNA content, and acinar proliferation were all blocked in Rcan1 overexpressing mice.We profile adaptive pancreatic growth, identify Rcan1 as an important new feedback regulator, and firmly establish that CN-NFAT signaling is required for this response."],"journal":["Gastroenterology"],"pubmed_title":["Regulator of calcineurin 1 controls growth plasticity of adult pancreas."],"pmcid":["PMC2929702"],"funding_grant_id":["T32 GM008322-19","R01 DK059578","R01 HL072016","T32 GM008322-18","T32 GM008322-17","R01 HL097768","P60 DK020572","DK52067","R01 DK052067","R01 DK059578-05","P60 DK020572-249013","5P60 DK20572","F32 DK077423","R01 DK059578-06A2","T32 GM008322","R21 DK068414","DK-0077423","P30 DK034933-219006","DK 59578","P30 DK034933","HL072016","P60 DK020572-259013","P30 DK-34933"],"pubmed_authors":["Ji B","Crozier SJ","Williams JA","Ernst SA","Rothermel BA","Gurda GT","Logsdon CD"],"additional_accession":[]},"is_claimable":false,"name":"Regulator of calcineurin 1 controls growth plasticity of adult pancreas.","description":"Growth of exocrine pancreas is regulated by gastrointestinal hormones, notably cholecystokinin (CCK). CCK-driven pancreatic growth requires calcineurin (CN), which activates Nuclear Factor of Activated T cells (NFATs), but the genetic underpinnings and feedback mechanisms that regulate this response are not known.Pancreatic growth was stimulated by protease inhibitor (PI)-containing chow, which induces secretion of endogenous CCK. Expression profiling of PI stimulation was performed on Affymetrix 430A chips, and CN was inhibited via FK506. Exocrine pancreas-specific overexpression of CN inhibitor Regulator of Calcineurin 1 (Rcan1) was achieved by breeding elastase-Cre(estrogen receptor [ER]) transgenics with \"flox-on\" Rcan1 mice.CN inhibitor FK506 blocked expression of 38 genes, as confirmed by quantitative polymerase chain reaction. The CN-dependent genes were linked to growth-related processes, whereas their promoters were enriched in NFAT and NFAT/AP1 sites. Multiple NFAT targets, including Rcan1, Rgs2, HB-EGF, Lif, and Gem, were validated by chromatin immunoprecipitation. One of these, a CN feedback inhibitor Rcan1, was induced >50 fold during 1-8 hours course of pancreatic growth and strongly inhibited (>99%) by FK506. To examine its role in pancreatic growth, we overexpressed Rcan1 in an inducible, acinar-specific fashion. Rcan1 overexpression inhibited CN-NFAT signaling, as shown using an NFAT-luciferase reporter and quantitative polymerase chain reaction. Most importantly, the increase in exocrine pancreas size, protein/DNA content, and acinar proliferation were all blocked in Rcan1 overexpressing mice.We profile adaptive pancreatic growth, identify Rcan1 as an important new feedback regulator, and firmly establish that CN-NFAT signaling is required for this response.","dates":{"release":"2010-01-01T00:00:00Z","publication":"2010 Aug","modification":"2021-02-20T05:33:33Z","creation":"2019-03-26T23:04:46Z"},"accession":"S-EPMC2929702","cross_references":{"pubmed":["20438729"],"doi":["10.1053/j.gastro.2010.04.050"]}}