Biological role of anaplastic lymphoma kinase in neuroblastoma
Biological role of anaplastic lymphoma kinase in neuroblastoma
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DOI：
10.1016/s0002-9440(10)62966-5
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发表时间：
2005-07-01
影响因子：
6
通讯作者：
Sakai, R
中科院分区：
文献类型：
--
作者：
Osajima-Hakomori, Y;Miyake, I;Sakai, R
间变性淋巴瘤激酶（ALK）是一种酪氨酸激酶受体，最初被鉴定为与间变性大细胞淋巴瘤相关的t（2;5）染色体重排中嵌合核磷蛋白-ALK蛋白的一部分。我们最近证明，ALK激酶是组成性激活的基因扩增在几个神经母细胞瘤细胞系的ALK基因座。活化的ALK与过度磷酸化的ShcC形成稳定的复合物，改变促分裂原活化蛋白激酶途径对生长因子的反应性。在本研究中，通过使用RNA干扰技术抑制神经母细胞瘤细胞系中ALK激酶的表达，检查了活化ALK的生物学作用。通过RNA干扰抑制神经母细胞瘤细胞中活化的ALX显著降低了ShcC、促分裂原活化蛋白激酶和Akt的磷酸化，诱导细胞快速凋亡。通过免疫组织化学分析，在大多数神经母细胞瘤组织样本中检测到ALK的胞浆表达，而在85例人神经母细胞瘤中仅观察到1例ALK显著扩增。样品这些数据表明，在神经母细胞瘤的真实的进展中，ALK激活的频率有限。
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor originally identified as part of the chimeric nucleophosmin-ALK protein in the t(2;5) chromosomal rearrangement associated with anaplastic large cell lymphoma. We recently demonstrated that the ALK kinase is constitutively activated by gene amplification at the ALK locus in several neuroblastoma cell lines. Forming a stable complex with hyperphosphorylated ShcC, activated ALK modifies the responsiveness of the mitogen-activated protein kinase pathway to growth factors. In the present study, the biological role of activated ALK was examined by suppressing the expression of ALK kinase in neuroblastoma cell lines using an RNA interference technique. The suppression of activated ALX in neuroblastoma cells by RNA interference significantly reduced the phosphorylation of ShcC, mitogen-activated protein kinases, and Akt, inducing rapid apoptosis in the cells. By immunohistochemical analysis, the cytoplasmic expression of ALK was detected in most of the samples of neuroblastoma tissues regardless of the stage of the tumor, whereas significant amplification of ALK was observed in only 1 of 85 cases of human neuroblastoma. samples. These data demonstrate the limited frequency of ALK activation in the real progression of neuroblastoma.