Profiling CCK-mediated pancreatic growth: the dynamic genetic program and the role of STATs as potential regulators.
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.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622, USA. ggurda1@jhmi.edu
Grzegorz T
GT
Gurda
Jackie Y
JY
Wang
LiLi
L
Guo
Stephen A
SA
Ernst
John A
JA
Williams
D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism / Q000494:pharmacology*; D016000:Cluster Analysis; D005215:Fasting / Q000378:metabolism / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D053263:Gene Regulatory Networks; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D046228:Microarray Analysis; D010179:Pancreas / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
D050791:STAT Transcription Factors; D002766:Cholecystokinin