Elevated JNK activation contributes to the pathogenesis of human brain tumors
Elevated JNK activation contributes to the pathogenesis of human brain tumors
复制标题
DOI：
10.1038/sj.onc.1205593
复制
发表时间：
2002-08-01
期刊：
影响因子：
8
通讯作者：
Wong, AJ
中科院分区：
文献类型：
--
作者：
Antonyak, MA;Kenyon, LC;Wong, AJ
ERK通路通常与EGF受体的活化相关，并已被证明在促进几种肿瘤表型中起主要作用。一种类似的信号模块，即JNK途径，尚未被证明可以被EGF受体持续激活，而是更均匀地受到细胞应激和细胞因子的刺激。JNK通路在原发性肿瘤中的功能尚不清楚，因为它在体外促进细胞凋亡和细胞生长，这可能是所选细胞系的反映。原发性人脑肿瘤经常表现出EGF受体的过度表达。为了阐明JNK在肿瘤发生中的作用，我们研究了JNK在大组原发性人脑肿瘤和肿瘤衍生细胞系中的作用。在这里，我们提出的证据表明，JNK在促进肿瘤发生在体内和体外的主要作用。蛋白质印迹分析表明，86%（18/21）的原发性脑肿瘤显示JNK激活的证据，但只有38%（8/21）显示ERK激活的证据。激酶分析显示，77%的脑肿瘤细胞系激活JNK响应EGF（7 13）或具有高水平的基础活性（3 13），而没有六个正常细胞系分析，包括星形胶质细胞，有这些特性。在几种生长因子中，EGF在肿瘤细胞系中产生最高水平的JNK诱导，并且激活的持续时间大于ERK。JNK的显性负性（dn）形式的表达有效地抑制EGF介导的锚定独立的生长和保护细胞死亡在两个胶质瘤细胞系。这些研究结果表明，增强JNK激活经常发现在原发性脑肿瘤，这种激活有助于转化相关的表型。
The ERK pathway is typically associated with activation of the EGF receptor and has been shown to play a major role in promoting several tumor phenotypes. An analogous signaling module, the JNK pathway, has not been shown to be consistently activated by the EGF receptor but is instead more uniformly stimulated by cellular stresses and cytokines. The function of the JNK pathway in primary tumors is unclear as it has been implicated in both promoting apoptosis and cell growth in vitro, which may be a reflection of the cell lines chosen. Primary human brain tumors frequently show overexpression of the EGF receptor. To clarify the role of JNK in tumorigenesis, we have investigated the role of JNK in a large panel of primary human brain tumors and tumor derived cell lines. Here we present evidence that JNK has a major role in promoting tumorigenesis both in vivo and in vitro. Western blot analysis demonstrated that 86% (18 of 21) of primary brain tumors showed evidence of JNK activation but only 38% (8 of 21) showed evidence of ERK activation. Kinase assays revealed that 77% of brain tumor cell lines activated JNK in response to EGF (7 of 13) or had high levels of basal activity (3 of 13), whereas none of six normal cell lines analysed, including astrocytes, had these properties. Of several growth factors examined, EGF produced the highest level of JNK induction in tumor cell lines and the duration of activation was greater than that seen for ERK. Expression of a dominant-negative (dn) form of JNK potently inhibited EGF mediated anchorage independent growth and protection from cell death in two glial tumor cell lines. These findings demonstrate that enhanced JNK activation is frequently found in primary brain tumors and that this activation contributes to phenotypes related to transformation.