Birsoy Kivanç, Chen Zhu, Friedman Jeffrey
Laboratory of Molecular Genetics, Rockefeller University, New York, NY 10021, USA.
Cell Metab. 2008 Apr;7(4):339-47. doi: 10.1016/j.cmet.2008.02.001.
While adipogenesis is known to be controlled by a complex network of transcription factors, less is known about the transcriptional cascade that initiates this process. We report here the characterization of Krüppel-like factor 4 (KLF4) as an essential early regulator of adipogenesis. Klf4 is expressed in 3T3-L1 cells within 30 min after exposure to a standard adipogenic cocktail of insulin, glucocorticoids, and IBMX. Knockdown of KLF4 inhibits adipogenesis and downregulates C/EBPbeta levels. KLF4 binds directly to the C/EBPbeta (Cebpb) promoter as shown by chromatin immunoprecipitation and gel shift assays and, together with Krox20, cooperatively transactivates a C/EBPbeta reporter. C/EBPbeta knockdown increases levels of KLF4 and Krox20, suggesting that C/EBPbeta normally suppresses Krox20 and KLF4 expression via a tightly controlled negative feedback loop. KLF4 is specifically induced in response to cAMP, which by itself can partially activate adipogenesis. These data suggest that KLF4 functions as an immediate early regulator of adipogenesis to induce C/EBPbeta.
虽然已知脂肪生成受复杂的转录因子网络控制，但对于启动这一过程的转录级联反应却知之甚少。我们在此报告Krüppel样因子4（KLF4）作为脂肪生成必需的早期调节因子的特征。在暴露于胰岛素、糖皮质激素和异丁基甲基黄嘌呤的标准脂肪生成混合物后30分钟内，Klf4在3T3-L1细胞中表达。敲低KLF4可抑制脂肪生成并下调C/EBPβ水平。染色质免疫沉淀和凝胶迁移实验表明，KLF4直接结合到C/EBPβ（Cebpb）启动子上，并且与Krox20一起协同反式激活C/EBPβ报告基因。敲低C/EBPβ会增加KLF4和Krox20的水平，这表明C/EBPβ通常通过严格控制的负反馈环抑制Krox20和KLF4的表达。KLF4是对cAMP特异性诱导的，而cAMP本身可部分激活脂肪生成。这些数据表明，KLF4作为脂肪生成的即时早期调节因子发挥作用以诱导C/EBPβ。
