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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Stem cell antigen-1 enhances tumorigenicity by disruption of growth differentiation factor-10 (GDFIO)-dependent TGF-β signaling
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Stem cell antigen-1 enhances tumorigenicity by disruption of growth differentiation factor-10 (GDFIO)-dependent TGF-β signaling

机译：干细胞抗原-1通过破坏生长分化因子10（GDFIO）依赖性TGF-β信号传导增强致瘤性

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摘要

Stem cell antigen (Sca)-1/Ly6A, a glycerophosphatidylinositol-linked surface protein, was found to be associated with murine stem cell- and progenitor cell-enriched populations, and also has been linked to the capacity of tumor-initiating cells. Despite these interesting associations, this protein's functional role in these processes remains largely unknown. To identify the mechanism underlying the protein's possible role in mammary tumorigenesis, Sca-1 expression was examined in Sca-1~+/EGFP mice during carcino-genesis. Mammary tumor cells derived from these mice readily engrafted in syngeneic mice, and tumor growth was markedly inhibited on down-regulation of Sca-1 expression. The latter effect was associated with significantly elevated expression of the TGF-p ligand growth differentiation factor-10 (GDF10), which was found to selectively activate TGF-β receptor (TβRI/ll)-dependent Smad3 phosphorylation. Overexpression of GDF10 attenuated tumor formation; conversely, silencing of GDF10 expression reversed these effects. Sca-1 attenuated GDF10-dependent TGF-β signaling by disrupting the heterodimerization of TβRI and TβRII receptors. These findings suggest a new functional role for Sca-1 in maintaining tumorigenicity, in part by acting as a potent suppressor of TGF-β signaling.
机译：发现干细胞抗原（Sca）-1 / Ly6A是一种与甘油磷脂酰肌醇连接的表面蛋白，与富含鼠干细胞和祖细胞的群体有关，并且还与引发肿瘤的细胞的能力有关。尽管存在这些有趣的关联，但在这些过程中该蛋白的功能作用仍然未知。为了确定蛋白质在乳腺肿瘤发生中可能作用的潜在机制，在癌变过程中检查了Sca-1〜+ / EGFP小鼠中Sca-1的表达。源自这些小鼠的乳腺肿瘤细胞易于移植到同系小鼠中，并且在Sca-1表达下调时肿瘤生长受到明显抑制。后者的作用与TGF-p配体生长分化因子10（GDF10）的表达显着升高有关，该表达因子可选择性激活TGF-β受体（TβRI/ II）依赖性Smad3磷酸化。 GDF10的过表达减弱了肿瘤的形成；相反，沉默GDF10表达可逆转这些影响。 Sca-1通过破坏TβRI和TβRII受体的异源二聚化作用，减弱了GDF10依赖性TGF-β信号传导。这些发现暗示了Sca-1在维持致瘤性方面的新功能作用，部分是通过充当TGF-β信号传导的有效抑制剂。

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    Geeta Upadhyay; Yuzhi Yin; Hongyan Yuan; Xin Li; Rik Derynck; Robert I. Glazer;

  • 作者单位

    Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, DC 20007;

    Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, DC 20007;

    Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, DC 20007;

    Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center, Washington, DC 20007;

    Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143;

    Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, DC 20007;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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