Peroxisome proliferator-activated receptor gamma and transforming growth factor-beta pathways inhibit intestinal epithelial cell growth by regulating levels of TSC-22.
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.
Gupta
Rajnish A
RA
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Sarraf
Pasha
P
Brockman
Jeffrey A
JA
Shappell
Scott B
SB
Raftery
Laurel A
LA
Willson
Timothy M
TM
DuBois
Raymond N
RN
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D019556:COS Cells; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology*; D005799:Genes, Dominant; D005822:Genetic Vectors; D006801:Humans; D017403:In Situ Hybridization; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D053554:Keratin-20; D008024:Ligands; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis*; D000077154:Rosiglitazone; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018076:DNA, Complementary; D007381:Intermediate Filament Proteins; C507499:KRT20 protein, human; D053554:Keratin-20; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C099726:TSC22D1 protein, human; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000077154:Rosiglitazone; D004247:DNA