Antonyak Marc A, Kenyon Lawrence C, Godwin Andrew K, James David C, Emlet David R, Okamoto Isamu, Tnani Mehdi, Holgado-Madruga Marina, Moscatello David K, Wong Albert J
The Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, PA 19107, USA.
Oncogene. 2002 Aug 1;21(33):5038-46. doi: 10.1038/sj.onc.1205593.
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.
ERK 通路通常与表皮生长因子（EGF）受体的激活相关，并且已被证明在促进多种肿瘤表型中起主要作用。一个类似的信号模块，即 JNK 通路，尚未被证明能被 EGF 受体持续激活，而是更多地被细胞应激和细胞因子均匀刺激。JNK 通路在原发性肿瘤中的功能尚不清楚，因为它在体外既与促进细胞凋亡有关，又与细胞生长有关，这可能反映了所选择的细胞系的情况。原发性人脑肿瘤经常显示出 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 在大量原发性人脑肿瘤和肿瘤衍生细胞系中的作用。在此我们提供证据表明，JNK 在体内和体外促进肿瘤发生中都起主要作用。蛋白质印迹分析表明，86%（21 个中有 18 个）的原发性脑肿瘤显示出 JNK 激活的证据，但只有 38%（21 个中有 8 个）显示出 ERK 激活的证据。激酶分析显示，77%的脑肿瘤细胞系对 EGF 有反应而激活 JNK（13 个中有 7 个）或具有高水平的基础活性（13 个中有 3 个），而所分析的六个正常细胞系，包括星形胶质细胞，均无这些特性。在所检测的几种生长因子中，EGF 在肿瘤细胞系中产生的 JNK 诱导水平最高，并且激活持续时间比 ERK 更长。JNK 的显性负性（dn）形式的表达在两种胶质肿瘤细胞系中有效抑制了 EGF 介导的不依赖贴壁生长和对细胞死亡的保护。这些发现表明，原发性脑肿瘤中经常发现 JNK 激活增强，并且这种激活促成了与转化相关的表型。
