The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling

Esha Mathew, Meredith A. Collins, Maite G. Fernandez-Barrena, Alexander M. Holtz, Wei Yan, James O. Hogan, Zachary Tata, Benjamin L. Allen, Martin E. Fernandez-Zapico, Marina Pasca Di Magliano

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Pancreatic cancer, one of the deadliest human malignancies, is almost uniformly associated with a mutant, constitutively active form of the oncogene Kras. Studies in genetically engineered mouse models have defined a requirement for oncogenic KRAS in both the formation of pancreatic intraepithelial neoplasias, the most common precursor lesions to pancreatic cancer, and in the maintenance and progression of these lesions. Previous work using an inducible model allowing tissue-specific and reversible expression of oncogenic Kras in the pancreas indicates that inactivation of this GTPase at the pancreatic intraepithelial neoplasia stage promotes pancreatic tissue repair. Here, we extend these findings to identify GLI1, a transcriptional effector of the Hedgehog pathway, as a central player in pancreatic tissue repair upon Kras inactivation. Deletion of a single allele of Gli1 results in improper stromal remodeling and perdurance of the inflammatory infiltrate characteristic of pancreatic tumorigenesis. Strikingly, this partial loss of Gli1 affects activated fibroblasts in the pancreas and the recruitment of immune cells that are vital for tissue recovery. Analysis of the mechanism using expression and chromatin immunoprecipitation assays identified a subset of cytokines, including IL-6, mIL-8, Mcp-1, and M-csf (Csf1), as direct GLI1 target genes potentially mediating this phenomenon. Finally, we demonstrate that canonical Hedgehog signaling, a known regulator of Gli1 activity, is required for pancreas recovery. Collectively, these data delineate a new pathway controlling tissue repair and highlight the importance of GLI1 in regulation of the pancreatic microenvironment during this cellular process.

Original languageEnglish (US)
Pages (from-to)27727-27743
Number of pages17
JournalJournal of Biological Chemistry
Volume289
Issue number40
DOIs
StatePublished - Oct 3 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Mathew, E., Collins, M. A., Fernandez-Barrena, M. G., Holtz, A. M., Yan, W., Hogan, J. O., Tata, Z., Allen, B. L., Fernandez-Zapico, M. E., & Di Magliano, M. P. (2014). The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling. Journal of Biological Chemistry, 289(40), 27727-27743. https://doi.org/10.1074/jbc.M114.556563