Regulator of calcineurin 1 controls growth plasticity of adult pancreas

Grzegorz T. Gurda, Stephen Crozier, Baoan Ji, Stephen A. Ernst, Craig D. Logsdon, Beverly A. Rothermel, John A. Williams

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Abstract

Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
JournalGastroenterology
Volume139
Issue number2
DOIs
StatePublished - Jan 1 2010

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All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Gurda, G. T., Crozier, S., Ji, B., Ernst, S. A., Logsdon, C. D., Rothermel, B. A., & Williams, J. A. (2010). Regulator of calcineurin 1 controls growth plasticity of adult pancreas. Gastroenterology, 139(2). https://doi.org/10.1053/j.gastro.2010.04.050