Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells
Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells
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DOI：
10.1016/s1535-6108(02)00214-3
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发表时间：
2002-12-01
期刊：
影响因子：
50.3
通讯作者：
Shannon, KM
中科院分区：
文献类型：
--
作者：
Donovan, S;See, W;Shannon, KM
Nf 1肿瘤抑制基因编码Ras的GTP酶激活蛋白。以前的工作涉及过度活跃的Ras在Nf 1缺陷细胞的异常生长，但是，有有限的数据，哪些效应调节特定的表型。为了解决这一问题，我们通过用编码截短的c-Myb等位基因的逆转录病毒感染胎肝细胞来产生骨髓细胞系。粒细胞-巨噬细胞集落刺激因子（GM-CSF）以剂量依赖性方式促进野生型Myb细胞的存活。相比之下，缺乏生长因子的Nf 1缺陷型骨髓细胞由于磷酸肌醇-3-OH激酶/蛋白激酶B级联的过度活化而对凋亡具有抗性。Nf 1（-/-）细胞也表现出生长因子非依赖性增殖和GM-CSF mRNA产生的上调，其依赖于Raf/ MEK/ERK信号传导。这些数据链接特定的Ras效应与离散的细胞表型在Nf 1缺陷细胞。
The Nf1 tumor suppressor encodes a GTPase-activating protein for Ras. Previous work has implicated hyperactive Ras in the aberrant growth of Nf1-deficient cells; however, there are limited data on which effectors modulate specific phenotypes. To address this, we generated myeloid cell lines by infecting fetal liver cells with a retrovirus encoding a truncated allele of c-Myb. Granulocyte-macrophage colony stimulating factor (GM-CSF) promoted the survival of wild-type Myb cells in a dose-dependent manner. By contrast, Nf1-deficient myeloid cells deprived of growth factors, were resistant to apoptosis due to hyperactivation of the phosphoinositide-3-OH kinase/protein kinase B cascade. Nf1(-/-) cells also demonstrated growth factor-independent proliferation and upregulation of GM-CSF mRNA production that were dependent upon Raf/ MEK/ERK signaling. These data link specific Ras effectors with discrete cellular phenotypes in Nf1-deficient cells.