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

J Biol Chem. 2003 Feb 28;278(9):7431-8. doi: 10.1074/jbc.M208076200. Epub 2002 Dec 4.


Peroxisome proliferator-activated receptor gamma (PPARgamma) and transforming growth factor-beta (TGF-beta) 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 PPARgamma to induce TSC-22 was not dependent on an intact TGF-beta1 signaling pathway and was specific for the gamma 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 PPARgamma or TGF-beta pathways. These results place TSC-22 as an important downstream component of PPARgamma and TGF-beta signaling during intestinal epithelial cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Northern
  • Blotting, Western
  • COS Cells
  • Cell Differentiation
  • Cell Division
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • DNA / metabolism
  • DNA, Complementary / metabolism
  • Dose-Response Relationship, Drug
  • Epithelial Cells / cytology*
  • Genes, Dominant
  • Genetic Vectors
  • Humans
  • In Situ Hybridization
  • Intermediate Filament Proteins / metabolism
  • Intestines / cytology*
  • Keratin-20
  • Ligands
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Precipitin Tests
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Repressor Proteins / biosynthesis*
  • Rosiglitazone
  • Signal Transduction
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Time Factors
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection
  • Transforming Growth Factor beta / metabolism*


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA, Complementary
  • Intermediate Filament Proteins
  • KRT20 protein, human
  • Keratin-20
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • TSC22D1 protein, human
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Transforming Growth Factor beta
  • Rosiglitazone
  • DNA