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-β（Peroxisome proliferator-activated receptor-β，PPAR-β）是一种由脂肪酸配体激活的脂质敏感转录因子.除了在脂质代谢中的作用外，PPAR-γ还参与细胞的分化和增殖，在代谢紊乱、动脉粥样硬化、纤维化和肿瘤发生中具有重要作用。我们已经发现了一个以前未知的作用，过氧化物酶体增殖物激活受体-γ在肿瘤间质。PPARb？/¿小鼠由于肿瘤血管形成缺陷而不能支持肿瘤生长，并且在肿瘤内皮细胞和肌成纤维细胞的分化中显示出显著的改变。PPARb/<$-小鼠中的肿瘤含有大量表达异常高水平的血管平滑肌α-2肌动蛋白（SMA）的基质细胞。在细胞培养物中，在没有完整的PPAR-binding DNA结合结构域的情况下，可以看到SMA启动子被PPAR-binding抑制，这表明了一种新的转录调控机制。目前的建议的目的是研究如何PPAR-beta发挥这种调节作用，特别是它如何影响与近端SMA启动子相互作用的转录因子（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酪氨酸调节基因中具有关键功能，因此我们的研究可能会对PPAR-酪氨酸在细胞分化和肿瘤基质调节中的作用产生普遍的见解。

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.