Collaborative Innovation Center of Tianjin Metabolic Diseases Hospital, Key Laboratory of Hormones and Development, Ministry of Health, Metabolic Diseases Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
2011 Collaborative Innovation Center for Metabolic Diseases, Metabolic Diseases Hospital, Tianjin Medical University, Tianjin, China.
FASEB J. 2018 Jun;32(6):3096-3107. doi: 10.1096/fj.201700830RR. Epub 2018 Jan 18.
Emerging evidence suggests that cysteine-rich protein 61 (CYR61) plays a role in the differentiation and development of chondrocytes, osteoblasts, and osteoclasts; however, little is known about its role in adipogenesis. The current study indicates that the expression level of Cyr61 was altered in primary cultured marrow stromal cells and the established mesenchymal cell line, C3H10T1/2, after adipogenic treatment. Overexpressing Cyr61 repressed C3H10T1/2 and primary marrow stromal cells to differentiate into mature adipocytes. Conversely, inhibition of endogenous Cyr61 induced C3H10T1/2 and primary marrow stromal cells to fully differentiate. Mechanism investigations reveal that knockdown of Cyr61 inhibited the nuclear translocation of β-catenin and decreased nuclear protein levels of β-catenin and transcription factor 7-like 2. Moreover, the silencing of Cyr61 increased protein levels of phosphorylated ribosomal protein S6 kinase B1, mammalian target of rapamycin, eukaryotic translation initiation factor 4E-binding protein 1, and ribosomal protein S6-the major components of mammalian target of rapamycin complex 1 (mTORC1) signaling-in C3H10T1/2 cells. Additional investigations demonstrated that treatment with rapamycin significantly attenuated adipocyte formation that was induced by Cyr61 small interfering RNA (siRNA) transfection. Moreover, Cyr61 siRNA also lost its ability to stimulate adipocyte formation under the background of β-catenin overexpression. Taken together, our study provides evidence that CYR61 regulates adipocyte differentiation via multiple signaling pathways that involve at least the inactivation of mTORC1 signaling and the activation of canonical Wnt signaling.-Yang, Y., Qi, Q., Wang, Y., Shi, Y., Yang, W., Cen, Y., Zhu, E., Li, X., Chen, D., Wang, B. Cysteine-rich protein 61 regulates adipocyte differentiation from mesenchymal stem cells through mammalian target of rapamycin complex 1 and canonical Wnt signaling.
新兴证据表明，富含半胱氨酸的蛋白 61（CYR61）在软骨细胞、成骨细胞和破骨细胞的分化和发育中发挥作用；然而，其在脂肪生成中的作用知之甚少。本研究表明，在脂肪生成处理后，原代培养骨髓基质细胞和已建立的间充质细胞系 C3H10T1/2 中的 Cyr61 表达水平发生改变。过表达 Cyr61 抑制 C3H10T1/2 和原代骨髓基质细胞分化为成熟脂肪细胞。相反，抑制内源性 Cyr61 诱导 C3H10T1/2 和原代骨髓基质细胞完全分化。机制研究表明，Cyr61 敲低抑制 β-连环蛋白的核易位，并降低 β-连环蛋白和转录因子 7 样 2 的核蛋白水平。此外，Cyr61 的沉默增加了磷酸化核糖体蛋白 S6 激酶 B1、雷帕霉素靶蛋白、真核翻译起始因子 4E 结合蛋白 1 和核糖体蛋白 S6 的蛋白水平——哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）信号通路的主要成分在 C3H10T1/2 细胞中。进一步的研究表明，雷帕霉素处理显著减弱了 Cyr61 小干扰 RNA（siRNA）转染诱导的脂肪细胞形成。此外，Cyr61 siRNA 在 β-连环蛋白过表达的背景下也失去了刺激脂肪细胞形成的能力。综上所述，我们的研究提供了证据表明，CYR61 通过至少涉及 mTORC1 信号失活和经典 Wnt 信号激活的多种信号通路调节脂肪细胞分化。
