The splicing-factor oncoprotein SF2/ASF activates mTORC1
The splicing-factor oncoprotein SF2/ASF activates mTORC1
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DOI：
10.1073/pnas.0801376105
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发表时间：
2008-10-07
影响因子：
11.1
通讯作者：
Krainer, Adrian R.
中科院分区：
文献类型：
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作者：
Karni, Rotem;Hippo, Yoshitaka;Krainer, Adrian R.
剪接因子SF2/ASF是一种癌蛋白，在许多癌症中上调，当略微过度表达时，可以转化成永生的啮齿动物成纤维细胞。MTOR信号通路在许多癌症中都被激活，该通路的药物阻滞剂正在作为抗癌药物进行临床试验。我们在SF2/ASF转化的细胞中检测了mTOR通路的活性，发现这种剪接因子激活了该通路的mTORC1分支，通过S6K和eIF4EBP1的磷酸化来测量。这种激活是mTORC1特异的，因为没有检测到mTORC2底物Akt的激活。SF2/ASF激活mTORC1绕过了上游的PI3K/Akt信号通路，这对sF2/ASF介导的转化是必不可少的，因为雷帕霉素抑制mTOR在体内外阻断了SF2/ASF的转化。此外，shRINA介导的mTOR或mTORC1和mTORC2组分Raptor和Rictor的特异性敲除，取消了过表达SF2/ASF的细胞的致瘤潜力。这些结果表明，SF2/ASF上调的临床肿瘤可能对mTOR抑制剂特别敏感。
The splicing factor SF2/ASF is an oncoprotein that is up-regulated in many cancers and can transform immortal rodent fibroblasts when slightly overexpressed. The mTOR signaling pathway is activated in many cancers, and pharmacological blockers of this pathway are in clinical trials as anticancer drugs. We examined the activity of the mTOR pathway in cells transformed by SF2/ASF and found that this splicing factor activates the mTORC1 branch of the pathway, as measured by S6K and eIF4EBP1 phosphorylation. This activation is specific to mTORC1 because no activation of Akt, an mTORC2 substrate, was detected. mTORC1 activation by SF2/ASF bypasses upstream PI3K/Akt signaling and is essential for SF2/ASF-mediated transformation, as inhibition of mTOR by rapamycin blocked transformation by SF2/ASF in vitro and in vivo. Moreover, shRINA-mediated knockdown of mTOR, or of the specific mTORC1 and mTORC2 components Raptor and Rictor, abolished the tumorigenic potential of cells overexpressing SF2/ASF. These results suggest that clinical tumors with SF2/ASF up-regulation could be especially sensitive to mTOR inhibitors.