Wang Yuhui, Sul Hei Sook
Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell Metab. 2009 Mar;9(3):287-302. doi: 10.1016/j.cmet.2009.01.013.
Pref-1 is an EGF repeat-containing transmembrane protein that produces a biologically active soluble form by TACE-mediated cleavage. Although Pref-1 inhibition of adipogenesis has been well established, the specific target(s) of Pref-1 or the Pref-1 function in mesenchymal cell commitment/differentiation are not known. Here, we show that Sox9 downregulation is required for adipocyte differentiation and that Pref-1 inhibits adipocyte differentiation through upregulating Sox9 expression. Sox9 directly binds to the promoter regions of C/EBPbeta and C/EBPdelta to suppress their promoter activity, preventing adipocyte differentiation. Furthermore, we also show that, by inducing Sox9, Pref-1 promotes chondrogenic induction of mesenchymal cells but prevents chondrocyte maturation as well as osteoblast differentiation, with supporting in vivo evidence in Pref-1 null and Pref-1 transgenic mice. Thus, Sox9 is a Pref-1 target, and Pref-1 directs multipotent mesenchymal cells to the chondrogenic lineage but inhibits differentiation into adipocytes as well as osteoblasts and chondrocytes.
Pref-1是一种含有表皮生长因子（EGF）重复序列的跨膜蛋白，可通过肿瘤坏死因子α转换酶（TACE）介导的切割产生具有生物活性的可溶性形式。尽管Pref-1对脂肪生成的抑制作用已得到充分证实，但Pref-1的具体靶点或Pref-1在间充质细胞定向分化中的功能尚不清楚。在此，我们表明脂肪细胞分化需要下调Sox9，且Pref-1通过上调Sox9表达来抑制脂肪细胞分化。Sox9直接结合C/EBPβ和C/EBPδ的启动子区域以抑制其启动子活性，从而阻止脂肪细胞分化。此外，我们还表明，Pref-1通过诱导Sox9促进间充质细胞向软骨细胞的诱导，但阻止软骨细胞成熟以及成骨细胞分化，这在Pref-1基因敲除和Pref-1转基因小鼠中得到了体内证据的支持。因此，Sox9是Pref-1的靶点，且Pref-1引导多能间充质细胞向软骨细胞谱系分化，但抑制其向脂肪细胞以及成骨细胞和软骨细胞的分化。
