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A PROLIFERATION SWITCH FOR GENETICALLY MODIFIED CELLS

机译:遗传修饰细胞的增殖开关

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摘要

Receptor dimerization is the key signaling event for many cytokines, including erythropoietin. A system has been recently developed that permits intracellular protein dimerization to be reversibly activated in response to a lipid-soluble dimeric form of the drug FK506, tailed FK1012. FK1012 is used as a pharmacological mediator of dimerization to bring together FK506 binding domains, taken from the endogenous protein FKBP12. In experiments reported herein, FK1012-induced dimerization of a fusion protein containing the intracellular portion of the erythropoietin receptor allowed cells normally dependent on interleukin 3 to proliferate in its absence, FK506 competitively reversed the proliferative effect of FK1012 but had no influence on the proliferative effect of interleukin 3. Signaling pathways activated by FK1012 mimicked those activated by erythropoietin, because both JAK2 and STAT5 were phosphorylated in response to FK1012. This approach may provide a means to specifically and reversibly stimulate the proliferation of genetically modified cell populations in vitro or in vivo. [References: 44]
机译:受体二聚化是许多细胞因子(包括促红细胞生成素)的关键信号转导事件。最近已经开发了一种系统,该系统允许细胞内蛋白质二聚化响应于药物FK506的脂溶性二聚体形式(尾部为FK1012)而可逆地被激活。 FK1012用作二聚化的药理介质,将来自内源性蛋白质FKBP12的FK506结合域聚集在一起。在本文报道的实验中,FK1012诱导的包含促红细胞生成素受体细胞内部分的融合蛋白的二聚化使正常情况下依赖白介素3的细胞在不存在时得以增殖,FK506竞争性地逆转了FK1012的增殖作用,但对增殖作用没有影响白介素3的表达。FK1012激活的信号通路模仿了促红细胞生成素激活的信号通路,因为JAK2和STAT5均响应于FK1012而被磷酸化。这种方法可以提供一种在体外或体内特异性和可逆地刺激转基因细胞群增殖的方法。 [参考:44]

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