Regulator of calcineurin 1 controls growth plasticity of adult pancreas

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 - 2010
Externally publishedYes

Fingerprint

Calcineurin
Pancreas
NFATC Transcription Factors
Growth
Exocrine Pancreas
Cholecystokinin
Tacrolimus
Protease Inhibitors
TCF Transcription Factors
Gastrointestinal Hormones
Polymerase Chain Reaction
Chromatin Immunoprecipitation
Pancreatic Elastase
Luciferases
Estrogen Receptors
Breeding

Keywords

  • Calcineurin
  • Growth
  • NFAT
  • Nuclear Factor of Activated T Cells
  • Pancreas
  • Rcan1
  • Regulator of Calcineurin 1

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Gurda, G. T., Crozier, S. J., Ji, B. D., 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

Regulator of calcineurin 1 controls growth plasticity of adult pancreas. / Gurda, Grzegorz T.; Crozier, Stephen J.; Ji, Baoan D; Ernst, Stephen A.; Logsdon, Craig D.; Rothermel, Beverly A.; Williams, John A.

In: Gastroenterology, Vol. 139, No. 2, 2010.

Research output: Contribution to journalArticle

Gurda, GT, Crozier, SJ, Ji, BD, Ernst, SA, Logsdon, CD, Rothermel, BA & Williams, JA 2010, 'Regulator of calcineurin 1 controls growth plasticity of adult pancreas', Gastroenterology, vol. 139, no. 2. https://doi.org/10.1053/j.gastro.2010.04.050
Gurda, Grzegorz T. ; Crozier, Stephen J. ; Ji, Baoan D ; Ernst, Stephen A. ; Logsdon, Craig D. ; Rothermel, Beverly A. ; Williams, John A. / Regulator of calcineurin 1 controls growth plasticity of adult pancreas. In: Gastroenterology. 2010 ; Vol. 139, No. 2.
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