Peroxisome proliferator-activated receptorG and ligands: pathways and functions

Peroxisome proliferator-activated receptor-γ and ligands: pathways and functions. PPARγ protein exhibits a structural organization consisting of three functional domains: an N-terminal domain, a DNA-binding domain (DBD) and a carboxy-terminal ligand binding domain (LBD). PPARγ forms heterodimers with a second member of the nuclear receptor family, the retinoic X receptor (RXR). Unliganded PPARγ suppresses transcription (pathway A) either by interfering with key transcription factors (pathway A1) or through recruitment of corepressors (CoRep) on a PPRE element (pathway A2). Ligand binding to PPARγ (pathway B) triggers conformational changes that lead to dissociation of corepressors (CoRep) and subsequent association of coactivators (CoAct). The complex is binding to PPREs and triggers transcription (pathway B). PPARs ligands can also exert their action through PPARγ-independent mechanisms also (pathway C). For instance in NSCLC cell lines activation of TNF-TRAIL induce apoptosis, while PGE2 degradation, trough 15-hydroxyprostagladin dehydrogenase induction, results in enhanced epithelial differentiation. In endothelial cells PPARγ ligands can markedly boost expression of CD36 which functions as the receptor of endogenous antiangiogenic molecule thrombospondin-1, thereby potentiating the apoptotic response. (PFAs: polyunsaturated fatty acids, TZDs: thiazolidinediones, PPRE: peroxisome proliferator response element, TNF: tumor necrosis factor, TRAIL: TNF-related apoptosis-inducing ligand, NSCLC: non-small cell lung carcinoma).

Publication

PPARγ: The Portrait of a Target Ally to Cancer Chemopreventive Agents. (2008) Ioannis Sainis, et al. PPAR Res. 2008;2008:436489. Figure: F1. All organisms Mus musculus Homo sapiens Rattus norvegicus Drosophila melanogaster Danio rerio

Disease mentions