Target genes of peroxisome proliferator-activated receptor gamma in colorectal cancer cells.
Activation of the nuclear hormone peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits cell growth and promotes differentiation in a broad spectrum of epithelial derived tumor cell lines. Here we utilized microarray technology to identify PPARgamma gene targets in intestinal epithelial cells. For each gene, the induction or repression was seen with two structurally distinct PPARgamma agonists, and the change in expression could be blocked by co-treatment with a specific PPARgamma antagonist. A majority of the genes could be regulated independently by a retinoid X receptor specific agonist. Genes implicated in lipid transport or storage (adipophilin and liver fatty acid-binding protein) were also activated by agonists of PPAR subtypes alpha and/or delta. In contrast, PPARgamma-selective targets included genes linked to growth regulatory pathways (regenerating gene IA), colon epithelial cell maturation (GOB-4 and keratin 20), and immune modulation (neutrophil-gelatinase-associated lipocalin). Additionally, three different genes of the carcinoembryonic antigen family were induced by PPARgamma. Cultured cells treated with PPARgamma ligands demonstrated an increase in Ca(2+)-independent, carcinoembryonic antigen-dependent homotypic aggregation, suggesting a potential role for PPARgamma in regulating intercellular adhesion. Collectively, these results will help define the mechanisms by which PPARgamma regulates intestinal epithelial cell biology.
Gupta
R A
RA
Departments of Medicine and Cell Biology, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee 37232, USA.
Brockman
J A
JA
Sarraf
P
P
Willson
T M
TM
DuBois
R N
RN
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D019556:COS Cells; D002448:Cell Adhesion; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000819:agonists; D047488:Retinoid X Receptors; D013997:Time Factors; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D008156:Luciferases