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

过氧化物酶体增殖激活受体-β (PPAR-β) 对血管平滑肌 α-肌动蛋白 (SMA) 基因的转录调节

• 批准号: 32254318
• 负责人: Professor Dr. Rolf Müller
• 金额: --
• 依托单位: Zentrum für Tumor- und Immunbiologie (ZTI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/32254318?language=en
• 关键词: Transcriptional; regulation; vascular; smooth; muscle

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.

过氧化物酶体增殖物激活受体-β（PPAR-β）作为由脂肪酸配体激活的脂质传感转录因子，除了在脂质代谢中发挥作用之外，PPAR-β还在细胞分化和增殖中起作用，并且在代谢紊乱、动脉粥样硬化中具有重要作用。我们发现了 PPAR-ß 在肿瘤基质中的一个先前未知的作用。 /¿小鼠由于肿瘤血管化缺陷而无法支持肿瘤的生长，并且 PPARb 中的肿瘤内皮细胞和肌成纤维细胞的分化发生了深刻的改变。 /¿ - 小鼠含有数量惊人的基质细胞，表达异常高水平的血管平滑肌 α-2 肌动蛋白 (SMA)。PPAR-β 对 SMA 启动子的抑制在细胞培养物中得到了重现，并且在缺乏完整 PPAR-β DNA 的情况下也可见到。 -结合域，指出转录调控的新机制，当前提案的目的是研究 PPAR-ß 如何发挥这种调控作用，特别是它如何影响与近端 SMA 相互作用的转录因子的相互作用。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功能，因此我们的研究可能会对 PPAR-ß 在细胞分化中的作用产生一般性的见解。和肿瘤基质调节。