PPAR- Agonists and Their Effects on IGF-I Receptor Signaling: Implications for Cancer
Figure 2
Components and signaling pathways of the PPAR system. (a) Schematic representation of components of the PPAR system. PPARs act as ligand-activated transcription factors that are responsive to the lipid status of the cell. The physiological ligands for these nuclear receptors are typically unsaturated fatty acids (FFAs) and their eicosanoid products. PPARs regulate the expression of genes that encode proteins involved with lipid metabolism (oxidation), leukotriene degradation, energy balance, eicosanoid signaling, cell differentiation and tumorigenesis. PPARs are differentially expressed in the various tissues. PPAR- is highly expressed in liver, kidney, heart, brown adipose tissue, and the intestine, whereas PPAR- is found in adipose tissue, small intestine, and lymphatic tissues. PPAR- is ubiquitous. (b) PPAR- genomic versus nongenomic actions . PPAR- belongs to the class of nuclear receptors, with a typical modular structure composed by at least an N-terminal transactivation domain and a DNA binding domain (DBD). Upon ligand binding, a conformational change leads to the release of corepressors (NCoRs), recruitment of coactivators (NCoAs), heterodimerization and transactivation of PPRE-related promoters. This genomic function of PPAR- controls immune response, as well as lipid and glucose metabolism. Nuclear PPAR- exerts also a negative cross-talk towards major proinflammatory and promitotic transcription factors. Cytoplasmic PPAR-, by interacting with proteins (MEK1, -catenin) and activating transmembrane proteinases, elicits rapid and transient nongenomic effects that modulate EGF-R transactivation, calcium influx, and PI3K/Akt, IKK/NFB and MAPKs signaling pathways.
