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

过氧化物酶体增殖物激活受体(PPAR-？)是一种由脂肪酸配体激活的脂敏转录因子。除了在脂质代谢中发挥作用外，PPAR还参与细胞的分化和增殖，并在代谢紊乱、动脉粥样硬化、纤维化和肿瘤发生中发挥重要作用。我们发现了PPAR-？在肿瘤间质中的一个以前未知的作用。PPARb？/？小鼠由于肿瘤血管的缺陷而不能支持肿瘤的生长，并在肿瘤内皮细胞和肌成纤维细胞的分化方面表现出深刻的变化。PPARb？/？小鼠的肿瘤含有数量惊人的间质细胞，表达异常高水平的血管平滑肌α-2肌动蛋白(SMA)。在细胞培养中，PPAR-？对SMA启动子的抑制被重述，并且在没有完整的PPAR-？DNA结合域的情况下看到，这表明了一种新的转录调控机制。本提案的目的是研究PPAR-ç如何发挥这种调节作用，特别是它如何影响转录因子与近端SMA启动子(SRF、C/EBP、KLF-4)的相互作用。由于这些转录因子在调节许多其他分化相关基因和细胞因子调节基因方面具有关键作用，我们的研究可能会对PPAR-？在细胞分化和肿瘤间质调节中的作用产生普遍的了解。

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.