Peroxisome proliferator-activated receptor γ and transforming growth factor-β pathways inhibit intestinal epithelial cell growth by regulating levels of TSC-22

Rajnish A. Gupta, Pasha Sarraf, Jeffrey A. Brockman, Scott B. Shappell, Laurel A. Raftery, Timothy M. Willson, Raymond N. DuBois

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) and transforming growth factor-β (TGF-β) are key regulators of epithelial cell biology. However, the molecular mechanisms by which either pathway induces growth inhibition and differentiation are incompletely understood. We have identified transforming growth factor-simulated clone-22 (TSC-22) as a target gene of both pathways in intestinal epithelial cells. TSC-22 is member of a family of leucine zipper containing transcription factors with repressor activity. Although little is known regarding its function in mammals, the Drosophila homolog of TSC-22, bunched, plays an essential role in fly development. The ability of PPARγ to induce TSC-22 was not dependent on an intact TGF-β1 signaling pathway and was specific for the γ isoform. Localization studies revealed that TSC-22 mRNA is enriched in the postmitotic epithelial compartment of the normal human colon. Cells transfected with wild-type TSC-22 exhibited reduced growth rates and increased levels of p21 compared with vector-transfected cells. Furthermore, transfection with a dominant negative TSC-22 in which both repressor domains were deleted was able to reverse the p21 induction and growth inhibition caused by activation of either the PPARγ or TGF-β pathways. These results place TSC-22 as an important downstream component of PPARγ and TGF-β signaling during intestinal epithelial cell differentiation.

Original languageEnglish (US)
Pages (from-to)7431-7438
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number9
DOIs
StatePublished - Feb 28 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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