Reverse crosstalk of TGF? and PPAR?/? signaling identified by transcriptional profiling.

ABSTRACT: Previous work has provided strong evidence for a role of peroxisome proliferator-activated receptor ?/? (PPAR?/?) and transforming growth factor-? (TGF?) in inflammation and tumor stroma function, raising the possibility that both signaling pathways are interconnected. We have addressed this hypothesis by microarray analyses of human diploid fibroblasts induced to myofibroblastic differentiation, which revealed a substantial, mostly reverse crosstalk of both pathways and identified distinct classes of genes. A major class encompasses classical PPAR target genes, including ANGPTL4, CPT1A, ADRP and PDK4. These genes are repressed by TGF?, which is counteracted by PPAR?/? activation. This is mediated, at least in part, by the TGF?-induced recruitment of the corepressor SMRT to PPAR response elements, and its release by PPAR?/? ligands, indicating that TGF? and PPAR?/? signals are integrated by chromatin-associated complexes. A second class represents TGF?-induced genes that are downregulated by PPAR?/? agonists, exemplified by CD274 and IL6, which is consistent with the anti-inflammatory properties of PPAR?/? ligands. Finally, cooperative regulation by both ligands was observed for a minor group of genes, including several regulators of cell proliferation. These observations indicate that PPAR?/? is able to influence the expression of distinct sets of both TGF?-repressed and TGF?-activated genes in both directions.

SUBMITTER: Stockert J 

PROVIDER: S-EPMC3017614 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature