Regulation of leukemic cell adhesion, proliferation, and survival by β-catenin
Regulation of leukemic cell adhesion, proliferation, and survival by β-catenin
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DOI：
10.1182/blood.v100.3.982
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发表时间：
2002-08-01
期刊：
影响因子：
20.3
通讯作者：
Trepel, JB
中科院分区：
文献类型：
--
作者：
Chung, EJ;Hwang, SG;Trepel, JB
在上皮细胞中，β-连环蛋白作为细胞-细胞粘附装置的组分和作为转录因子的TCF/LEF（T细胞转录因子/淋巴增强子结合因子）家族的共激活物发挥关键作用。β-连环蛋白的失调与上皮来源细胞的恶性转化有关。然而，β-连环蛋白在血液恶性肿瘤中的功能尚未报道。β-连环蛋白在正常的外周血T细胞中检测不到，但在T-急性淋巴母细胞白血病细胞和其它造血来源的肿瘤细胞系中以及在初级淋巴样和髓样白血病细胞中表达。在Jurkat T-急性淋巴母细胞白血病细胞中检测β-连环蛋白功能。显性阴性β-连环蛋白或显性阴性TCF的过表达减少β-连环蛋白核信号传导并抑制Jurkat增殖和克隆形成。类似地，这些构建体抑制K562和HUT-102细胞的增殖。用β-连环蛋白反义下调Jurkat细胞对植物血凝素的粘附，减少β-连环蛋白表达。用抗Fas抗体孵育Jurkat细胞诱导β-连环蛋白N-和C-末端区域的半胱天冬酶依赖性有限蛋白水解，以及β-连环蛋白快速重新分布到洗涤剂不溶性细胞骨架，伴随着核β-连环蛋白信号传导的显著下降。Fas介导的细胞凋亡通过抑制β-连环蛋白核信号而增强。这些数据表明，R-连环蛋白可以在促进白血病细胞增殖，粘附和存活中发挥重要作用。(C)2002年，美国血液学会。
In epithelial cells beta-catenin plays a critical role as a component of the cell-cell adhesion apparatus and as a coactivator of the TCF/LEF (T-cell transcription factor/lymphoid enhancer binding factor) family of transcription factors. Deregulation of beta-catenin has been implicated in the malignant transformation of cells of epithelial origin. However, a function for beta-catenin in hematologic malignancies has not been reported. beta-Catenin is not detectable in normal peripheral blood T cells but is expressed in T-acute lymphoblastic leukemia cells and other tumor lines of hematopoietic origin and in primary lymphoid and myeloid leukemia cells. beta-Catenin function was examined in Jurkat T-acute lymphoblastic leukemia cells. Overexpression of dominant-negative beta-catenin or dominant-negative TCF reduced beta-catenin nuclear signaling and inhibited Jurkat proliferation and clonogenicity. Similarly, these constructs inhibited proliferation of K562 and HUT-102 cells. Reduction of beta-catenin expression with beta-catenin antisense down-regulated adhesion of Jurkat cells in response to phytolhemagglutinin. Incubation of Jurkat cells with anti-Fas induced caspase-dependent limited proteolysis of beta-catenin N- and C-terminal regions and rapid redistribution of beta-catenin to the detergent-insoluble cytoskeleton, concomitant with a marked decline in nuclear beta-catenin signaling. Fas-mediated apoptosis was potentiated by inhibition of beta-catenin nuclear signaling. The data suggest that R-catenin can play a significant role in promoting leukemic cell proliferation, adhesion, and survival. (C) 2002 by The American Society of Hematology.