Profiling CCK-mediated pancreatic growth: the dynamic genetic program and the role of STATs as potential regulators

Physiol Genomics. 2012 Jan 18;44(1):14-24. doi: 10.1152/physiolgenomics.00255.2010. Epub 2011 Oct 18.


Feeding mice with protease inhibitor (PI) leads to increased endogenous cholecystokinin (CCK) release and results in pancreatic growth. This adaptive response requires calcineurin (CN)-NFAT and AKT-mTOR pathways, but the genes involved, the dynamics of their expression, and other regulatory pathways remain unknown. Here, we examined the early (1-8 h) transcriptional program that underlies pancreatic growth. We found 314 upregulated and 219 downregulated genes with diverse temporal and functional profiles. Several new identifications include the following: stress response genes Gdf15 and Txnip, metabolic mediators Pitpnc1 and Hmges2, as well as components of growth factor response Fgf21, Atf3, and Egr1. The genes fell into seven self-organizing clusters, each with a distinct pattern of expression; a representative gene within each of the upregulated clusters (Egr1, Gadd45b, Rgs2, and Serpinb1a) was validated by qRT-PCR. Genes up at any point throughout the time course and CN-dependent genes were subjected to further bioinformatics-based networking and promoter analysis, yielding STATs as potential transcriptional regulators. As shown by PCR, qPCR, and Western blots, the active phospho-form of STAT3 and the Jak-STAT feedback inhibitor Socs2 were both increased throughout early pancreatic growth. Moreover, immunohistochemistry showed a CCK-dependent and acinar cell-specific increase in nuclear localization of p-STAT3, with >75% nuclear occupancy in PI-fed mice vs. <0.1% in controls. Thus, the study identified novel genes likely to be important for CCK-driven pancreatic growth, characterized and biologically validated the dynamic pattern of their expression and investigated STAT-Socs signaling as a new player in this trophic response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cholecystokinin / metabolism
  • Cholecystokinin / pharmacology*
  • Cluster Analysis
  • Fasting / metabolism
  • Fasting / physiology
  • Gene Expression Profiling
  • Gene Expression Regulation* / drug effects
  • Gene Expression Regulation* / genetics
  • Gene Regulatory Networks
  • Male
  • Mice
  • Mice, Inbred ICR
  • Microarray Analysis
  • Pancreas / drug effects*
  • Pancreas / growth & development*
  • Pancreas / metabolism
  • STAT Transcription Factors / metabolism
  • STAT Transcription Factors / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Time Factors


  • STAT Transcription Factors
  • Cholecystokinin