...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Oncogene >Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis
【24h】

Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis

机译：定义MDA-MB-231细胞肿瘤生长和转移所需的MAP3激酶

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Analysis of patient tumors suggests that multiple MAP3 kinases (MAP3Ks) are critical for growth and metastasis of cancer cells. MAP3Ks selectively control the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK), p38 and ERK5 in response to receptor tyrosine kinases and GTPases. We used MDA-MB-231 cells because of their ability to metastasize from the breast fat pad to distant lymph nodes for an orthotopic xenograft model to screen the function of seven MAP3Ks in controlling tumor growth and metastasis. Stable short hairpin RNA (shRNA) knockdown was used to inhibit the expression of each of the seven MAP3Ks, which were selected for their differential regulation of the MAPK network. The screen identified two MAP3Ks, MEKK2 and MLK3, whose shRNA knockdown caused significant inhibition of both tumor growth and metastasis. Neither MEKK2 nor MLK3 have been previously shown to regulate tumor growth and metastasis in vivo . These results demonstrated that MAP3Ks, which differentially activate JNK, p38 and ERK5, are necessary for xenograft tumor growth and metastasis of MDA-MB-231 tumors. The requirement for MAP3Ks signaling through multiple MAPK pathways explains why several members of the MAPK network are activated in cancer. MEKK2 was required for epidermal growth factor receptor and Her2/Neu activation of ERK5, with ERK5 being required for metastasis. Loss of MLK3 expression increased mitotic infidelity and apoptosis in vitro. Knockdown of MEKK2 and MLK3 resulted in increased apoptosis in orthotopic xenografts relative to control tumors in mice, inhibiting both tumor growth and metastasis; MEKK2 and MLK3 represent untargeted kinases in tumor biology for potential therapeutic development.
机译：对患者肿瘤的分析表明，多种MAP3激酶（MAP3Ks）对于癌细胞的生长和转移至关重要。 MAP3Ks选择性控制细胞外信号调节激酶1/2（ERK1 / 2），Jun N端激酶（JNK），p38和ERK5的激活，以响应受体酪氨酸激酶和GTPases。我们使用MDA-MB-231细胞是因为它们能够从乳腺脂肪垫转移到远处的淋巴结，用于原位异种移植模型，以筛选7种MAP3K在控制肿瘤生长和转移中的功能。稳定的短发夹RNA（shRNA）敲低被用来抑制七个MAP3K的表达，这是由于它们对MAPK网络的差异调节而选择的。该筛查确定了两个MAP3K，MEKK2和MLK3，其shRNA敲低可显着抑制肿瘤的生长和转移。先前未显示MEKK2和MLK3均在体内调节肿瘤的生长和转移。这些结果表明，差异激活JNK，p38和ERK5的MAP3Ks对于异种移植瘤的生长和MDA-MB-231肿瘤的转移是必需的。通过多个MAPK途径对MAP3Ks信号的需求解释了为什么MAPK网络的几个成员在癌症中被激活。表皮生长因子受体和ERK5的Her2 / Neu激活需要MEKK2，而转移需要ERK5。 MLK3表达的丧失在体外增加了有丝分裂的不忠和细胞凋亡。抑制MEKK2和MLK3导致原位异种移植物相对于小鼠对照肿瘤细胞凋亡增加，从而抑制了肿瘤的生长和转移。 MEKK2和MLK3代表了肿瘤生物学中潜在的治疗发展目标激酶。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号