Transcriptional regulation of the vascular smooth muscle alpha-actin (SMA) gene by the peroxisome-proliferatior activated receptor-beta (PPAR-beta)

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Peroxisome proliferator-activated receptor-ß (PPAR-ß) functions as a lipidsensing transcription factor activated by fatty acid ligands. Besides a role in lipid metabolism PPAR-ß figures in cell differentiation and proliferation, and has important functions in metabolic disorders, atherosclerosis, fibrosis and tumorigenesis. We have uncovered a previously unknown role for PPAR-ß in the tumor stroma. PPARb¿/¿ mice fail to support the growth of tumors due to a defect in tumor vascularization and show profound alterations in the differentiation of both tumor endothelial cells and myofibroblasts. Tumors in PPARb¿/¿- mice contain striking numbers of stroma cells expressing abnormally high levels of vascular smooth muscle alpha-2 actin (SMA). Repression of the SMA promoter by PPAR-ß was recapitulated in cell culture and seen in the absence of an intact PPAR-ß DNA-binding domain, pointing to a novel mechanism of transcriptional regulation. The purpose of the current proposal is to investigate how PPAR-ß exerts this regulatory effect and in particular how it influences the interplay of the transcription factors interacting with the proximal SMA promoter (SRF, C/EBP, KLF-4). Since these transcription factors have pivotal functions in regulating many other differentiation-associated and cytokine-regulated genes our study is likely to yield general insights into the role of PPAR-ß in cell differentiation and tumor stroma regulation.