Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma.
Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma.
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DOI：
10.1038/sj.bjc.6605184
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发表时间：
2009-08-04
影响因子：
8.8
通讯作者：
Kratzke RA
中科院分区：
文献类型：
--
作者：
Jacobson BA;De A;Kratzke MG;Patel MR;Jay-Dixon J;Whitson BA;Sadiq AA;Bitterman PB;Polunovsky VA;Kratzke RA
胰岛素样生长因子（IGF）-I信号刺激恶性间皮瘤和其他肿瘤类型的增殖，生存和侵袭。研究发现，肿瘤发生与帽依赖性蛋白质翻译的失调有关。IGF刺激对间皮瘤细胞系中帽介导的翻译激活的影响使用与合成的7-甲基GTP-cap类似物的结合测定进行了研究。此外，帽介导的翻译在这些细胞中被遗传抑制，具有4 E-BP 1的主导活性动机。在大多数间皮瘤细胞系中，IGF-I刺激导致4 E-BP 1与正常间皮瘤细胞相比过度磷酸化介导的失活。Akt的抑制剂减少IGF-I介导的4 E-BP 1磷酸化，而抑制MAPK信号传导没有这种效果。IGF-I刺激导致帽介导的翻译复合物的活化，如帽亲和力测定中增加的eIF 4G/eIF 4 E比率所示。Akt抑制逆转了eIF 4G/eIF 4 E比率。用活化的4 E-BP 1蛋白（4 E-BP 1A 37/A46）转染的间皮瘤细胞对IGF-I介导的生长、运动和集落形成具有抗性。在小鼠异种移植模型中，与对照肿瘤相比，表达显性活性4 E-BP 1A 37/A46阻遏蛋白的间皮瘤细胞显示出废除的致瘤性。间皮瘤细胞中的IGF-I信号传导通过其通过PI 3 K/Akt/mTOR信号传导激活帽介导的蛋白翻译复合物的能力驱动细胞增殖、运动性和肿瘤发生。
Insulin-like growth factor (IGF)-I signalling stimulates proliferation, survival, and invasion in malignant mesothelioma and other tumour types. Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation. The effect of IGF stimulation on cap-mediated translation activation in mesothelioma cell lines was studied using binding assays to a synthetic 7-methyl GTP-cap analogue. In addition, cap-mediated translation was genetically repressed in these cells with a dominant active motive of 4E-BP1. In most mesothelioma cell lines, IGF-I stimulation resulted in a hyperphosphorylation-mediated inactivation of 4E-BP1 compared with that in normal mesothelial cells. An inhibitor of Akt diminished IGF-I-mediated phosphorylation of 4E-BP1, whereas inhibiting MAPK signalling had no such effect. IGF-I stimulation resulted in the activation of the cap-mediated translation complex as indicated by an increased eIF4G/eIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4G/eIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1A37/A46) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1A37/A46 repressor protein showed abrogated tumourigenicity compared with control tumours. IGF-I signalling in mesothelioma cells drives cell proliferation, motility, and tumourigenesis through its ability to activate cap-mediated protein translation complex through PI3K/Akt/mTOR signalling.
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