Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors
Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors
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DOI：
10.1038/sj.onc.1202367
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发表时间：
1999-01-21
期刊：
影响因子：
8
通讯作者：
Kohno, M
中科院分区：
文献类型：
--
作者：
Hoshino, R;Chatani, Y;Kohno, M
41-kDa 和 43-kDa 丝裂原激活蛋白 (MAP) 激酶在有丝分裂信号转导途径中发挥着关键作用，是 MAP 激酶级联的重要组成部分，其中包括 MAP 激酶激酶 (MEK) 和 Raf-l。由于 Pas 和 Raf-l 等信号转导分子的异常激活与癌症有关，我们检查了 41-/43-kDa MAP 激酶的组成型激活是否与癌症相关。与来自各种人体器官的 138 种肿瘤细胞系和 102 种原发性肿瘤的肿瘤表型相关。在 50 个肿瘤细胞系 (36.2%) 中观察到 MAP 激酶的组成性激活，其方式相当具有组织特异性：来自胰腺、结肠、肺、卵巢和肾的细胞系表现出特别高的频率，具有高度的 MAP 激酶激活，而来自脑、食道、胃、肝脏和造血来源的细胞系则表现出较低的频率，具有有限程度的 MAP 激酶激活。我们还在相对大量源自肾、结肠和肺组织但不源自肝组织的原发性人类肿瘤中检测到 41-/43-kDa MAP 激酶的组成型激活。许多仅检测到 vas 基因点突变的肿瘤细胞显示出 MAP 激酶的组成型激活，然而，这一观察结果也有许多例外。相反，在大多数肿瘤细胞中，41-/43-kDa MAP激酶的激活伴随着Raf-l的激活，并且与所有检查的肿瘤细胞中MEK和p90(rsk)的激活完全相关。这些结果表明，肿瘤细胞中41-/43-kDa MAP激酶的组成性激活不是由于MAP激酶本身的紊乱，而是由于Raf-l的紊乱， Pas，或 Ras 上游的一些其他信号分子。
The 41-kDa and 43-kDa mitogen-activated protein (MAP) kinases play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAP kinase cascade, which includes MAP kinase kinase (MEK) and Raf-l, As aberrant activation of signal transducing molecules such as Pas and Raf-l has been linked with cancer, we examined whether constitutive activation of the 41-/43-kDa MAP kinases is associated with the neoplastic phenotype of 138 tumor cell lines and 102 primary tumors derived from various human organs. Constitutive activation of the MAP kinases was observed in 50 tumor cell lines (36.2%) in a rather tissue-specific manner: cell lines derived from pancreas, colon, lung, ovary and kidney showed especially high frequencies with a high degree of MAP kinase activation, while those derived from brain, esophagus, stomach, liver and of hematopoietic origin showed low frequencies with a limited degree of MAP kinase activation. We also detected constitutive activation of the 41-/43-kDa MAP kinases in a relatively large number of primary human tumors derived from kidney, colon and lung tissues but not from liver tissue. Many tumor cells, in which point mutations of vas genes mere detected, showed constitutive activation of MAP kinases, however, there were also many exceptions to this observation. In contrast, the activation of the 41-/43-kDa MAP kinases was accompanied by the activation of Raf-l in the majority of tumor cells and was completely associated with the activation of MEK and p90(rsk) in all the tumor cells examined, These results suggest that the constitutive activation of 41-/43-kDa MAP kinases in tumor cells is not due to the disorder of MAP kinases themselves, but is due to the disorder of Raf-l, Pas, or some other signaling molecules upstream of Ras.