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首页> 外文期刊>Molecular and Cellular Biology >Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.
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Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.

机译：非霍奇金淋巴瘤相关的NPM-间变性淋巴瘤激酶融合蛋白的核磷蛋白（NPM）部分在肿瘤发生中的作用。

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The NPM-ALK fusion gene, formed by the t(2;5)(p23;q35) translocation in non-Hodgkin's lymphoma, encodes a 75-kDa hybrid protein that contains the amino-terminal 117 amino acid residues of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase). Here, we demonstrate the transforming ability of NPM-ALK and show that oncogenesis by the chimeric protein requires the activation of its kinase function as a result of oligomerization mediated by the NPM segment. Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM. Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments. Immunostaining performed with both polyclonal and monoclonal anti-ALK antibodies confirmed the dual location of the oncoprotein and also indicated that NPM-ALK is abundant within both the nucleoplasm and the nucleolus. An intact NPM segment is absolutely required for NPM-ALK-mediated oncogenesis, as indicated by our observation that three different NPM-ALK mutant proteins lacking nonoverlapping portions of the NPM segment were each unable to form complexes, lacked kinase activity in vivo, and failed to transform cells. However, NPM could be functionally replaced in the fusion protein with the portion of the unrelated translocated promoter region (TPR) protein that activates the TPR-MET fusion kinase by mediating dimerization through its leucine zipper motif. This engineered TPR-ALK hybrid protein, which transformed cells almost as efficiently as NPM-ALK, was localized solely within the cytoplasm of cells. These data indicate that the nuclear and nucleolar localization of NPM-ALK, which probably occur because of transport via the shuttling activity of NPM, is not required for oncogenesis. Further, the activation of the truncated ALK protein by a completely heterologous oligomerization domain suggests that the functionally important role of the NPM segment of NPM-ALK in transformation is restricted to the formation of kinase-active oligomers and does not involve the alteration of normal NPM functions.
机译：NPM-ALK融合基因由非霍奇金淋巴瘤中的t（2; 5）（p23; q35）易位形成，编码一个75 kDa的杂合蛋白，其中包含核仁磷蛋白核磷蛋白的氨基末端117个氨基酸残基（NPM）连接到受体酪氨酸激酶ALK（间变性淋巴瘤激酶）的整个细胞质部分。在这里，我们展示了NPM-ALK的转化能力，并显示了嵌合蛋白的致癌作用需要激活其激酶功能，这是由NPM片段介导的寡聚作用的结果。沉降梯度实验表明，NPM-ALK形成体内约200 kDa或更大的多聚体复合物，其中也包含正常NPM。含有t（2; 5）易位的淋巴瘤细胞系SUP-M2的细胞分级研究表明NPM-ALK位于细胞质和核区室中。用多克隆抗体和单克隆抗ALK抗体进行的免疫染色证实了癌蛋白的双重定位，也表明NPM-ALK在核质和核仁中都丰富。完整的NPM片段对于NPM-ALK介导的致癌作用是绝对必需的，正如我们的观察所表明的那样，缺少NPM片段的非重叠部分的三种不同的NPM-ALK突变蛋白均不能形成复合物，体内缺乏激酶活性并且失败。转化细胞。然而，融合蛋白中的NPM可以在功能上被无关的易位启动子区域（TPR）蛋白的一部分所取代，后者通过介导亮氨酸拉链基序的二聚作用来激活TPR-MET融合激酶。这种工程改造的TPR-ALK杂合蛋白几乎可以像NPM-ALK一样有效地转化细胞，仅位于细胞质内。这些数据表明，发生肿瘤不需要NPM-ALK的核和核仁定位，这可能是由于通过NPM的穿梭活性进行转运所致。此外，通过完全异源的寡聚化结构域对截短的ALK蛋白的激活表明NPM-ALK的NPM片段在转化中的功能性重要作用仅限于激酶活性寡聚物的形成，并且不涉及正常NPM的改变职能。

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