...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular and Cellular Biology >8p12 Stem Cell Myeloproliferative Disorder: the FOP-Fibroblast Growth Factor Receptor 1 Fusion Protein of the t(6;8) Translocation Induces Cell Survival Mediated by Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt/mTOR Pathways
【24h】

8p12 Stem Cell Myeloproliferative Disorder: the FOP-Fibroblast Growth Factor Receptor 1 Fusion Protein of the t(6;8) Translocation Induces Cell Survival Mediated by Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt/mTOR Pathways

机译：8p12干细胞骨髓增生性疾病：t（6; 8）易位的FOP-成纤维细胞生长因子受体1融合蛋白诱导丝裂原活化的蛋白激酶和磷脂酰肌醇3-激酶/ Akt / mTOR途径介导的细胞存活。

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

摘要

The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
机译：FOP-成纤维细胞生长因子受体1（FGFR1）融合蛋白的表达是t（6; 8）（q27; p12）易位与干细胞骨髓增生性疾病伴淋巴瘤，髓样增生和嗜酸性粒细胞增多相关的结果。在本报告中，我们表明FOP的富亮氨酸N端区域与FGFR1催化域的融合导致鼠类造血细胞系Ba / F3通过抗凋亡作用转化为非因子依赖性细胞存活。这种存活作用取决于FOP-FGFR1的组成型酪氨酸磷酸化。在表达FOP-FGFR1的细胞中观察到STAT1和STAT3而非STAT5的磷酸化。 FOP-FGFR1的生存功能被磷脂酶Cγ结合位点的突变所废除。丝裂原激活的蛋白激酶（MAPK）在表达FOP-FGFR1的细胞中也被激活，并赋予造血细胞非细胞因子非依赖性的存活。这些结果表明，通过使用与野生型FGFR1相同的效应子，FOP-FGFR1能够保护细胞免于凋亡。此外，我们表明FOP-FGFR1磷酸化磷脂酰肌醇3（PI3）激酶和AKT，并且PI3激酶的特定抑制剂损害其促进细胞存活的能力。另外，表达FOP-FGFR1的细胞显示翻译p70S6激酶的阳性调节子的组成型磷酸化。 PI3-激酶和mTOR（雷帕霉素的哺乳动物靶标）抑制剂可抑制这种磷酸化。这些结果表明翻译控制对于介导FOP-FGFR1诱导的细胞存活作用是重要的。最后，FOP-FGFR1通过生存信号（包括BCL2过表达和caspase-9活性失活）保护细胞免于凋亡。阐明FOP-FGFR1组成性激活下游的信号传递事件，提供了对该致癌融合蛋白介导的白血病发生机制的深入了解。

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