Cytoplasmic localization of the oncogenic protein Ski in human cutaneous melanomas in vivo: functional implications for transforming growth factor beta signaling.
Cytoplasmic localization of the oncogenic protein Ski in human cutaneous melanomas in vivo: functional implications for transforming growth factor beta signaling.
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发表时间：
2001-11
期刊：
影响因子：
11.2
通讯作者：
J. Reed;E. Bales;Weidong Xu;Nihal A. Okan;D. Bandyopadhyay;E. Medrano
中科院分区：
文献类型：
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作者：
J. Reed;E. Bales;Weidong Xu;Nihal A. Okan;D. Bandyopadhyay;E. Medrano
致癌蛋白Ski与Smad蛋白结合，并抵消它们响应于转化生长因子β（TGF-β）的基因表达激活和生长抑制。在这里，我们表明Ski蛋白水平在体内分析的所有44个人黑色素瘤肿瘤组织中增加。此外，Ski亚细胞定位从浸润前黑色素瘤（原位黑色素瘤）的细胞核变化到原发性浸润性和转移性黑色素瘤的细胞核和细胞质。此外，Ski/Smad在细胞质中的关联似乎阻止了响应于TGF-β的Smad 3核转位。通过显示反义Ski载体下调Ski水平恢复TGF-β介导的生长抑制，确立了Ski过表达在黑素瘤中的生物学意义。这种抑制作用显然是通过上调细胞周期蛋白依赖性激酶-I p21（Waf-1）和抑制细胞周期蛋白依赖性激酶2活性介导的。我们的研究结果表明，高水平的Ski在人类黑色素瘤中产生破坏TGF-β信号表型类似于在TGF-β受体或Smad蛋白中携带突变的细胞，这可能代表了体内黑色素瘤进展中的一个重要事件。
The oncogenic protein Ski associates with Smad proteins and counteracts their activation of gene expression and growth inhibition in response to transforming growth factor beta (TGF-beta). Here we show that Ski protein levels are increased in all 44 human melanoma tumor tissues analyzed in vivo. In addition, Ski subcellular localization changes from nuclear, in preinvasive melanomas (melanomas in situ), to nuclear and cytoplasmic in primary invasive and metastatic melanomas. Furthermore, Ski/Smad association in the cytoplasm seems to prevent Smad3 nuclear translocation in response to TGF-beta. The biological significance of Ski overexpression in melanomas was established by showing that down-regulation of Ski levels, by antisense Ski vectors, restored TGF-beta-mediated growth inhibition. Such inhibition is apparently mediated by up-regulation of the cyclin-dependent kinase-I p21(Waf-1) and inhibition of cyclin-dependent kinase 2 activity. Our results suggest that high levels of Ski in human melanomas produce a disruption of TGF-beta signaling phenotypically similar to that in cells harboring mutations in TGF-beta receptors or Smad proteins, and this may represent a significant event in the progression of melanomas in vivo.