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首页> 外文期刊>Molecular and Cellular Biology >Hypergrowth mTORC1 Signals Translationally Activate the ARF Tumor Suppressor Checkpoint
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Hypergrowth mTORC1 Signals Translationally Activate the ARF Tumor Suppressor Checkpoint

机译：超生长mTORC1信号可翻译激活ARF肿瘤抑制物检查点

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The ARF tumor suppressor is a potent sensor of hyperproliferative cues emanating from oncogenic signaling. ARF responds to these cues by eliciting a cell cycle arrest, effectively abating the tumorigenic potential of these stimuli. Prior reports have demonstrated that oncogenic RasV12 signaling induces ARF through a mechanism mediated by the Dmp1 transcription factor. However, we now show that ARF protein is still induced in response to RasV12 in the absence of Dmp1 through the enhanced translation of existing Arf mRNAs. Here, we report that the progrowth Ras/tuberous sclerosis complex (TSC)/mTORC1 signaling pathway regulates ARF protein expression and triggers ARF-mediated tumor suppression through a novel translational mechanism. Hyperactivation of mTORC1 through Tsc1 loss resulted in a significant increase in ARF expression, activation of the p53 pathway, and a dramatic cell cycle arrest, which were completely reversed upon Arf deletion. ARF protein induced from RasV12 in the absence of Dmp1 repressed anchorage-independent colony formation in soft agar and tumor burden in an allograft model. Taken together, our data demonstrate the ability of the ARF tumor suppressor to respond to hypergrowth stimuli to prevent unwarranted tumor formation.
机译：ARF抑癌剂是一种强大的传感器，可以指示由致癌信号产生的过度增殖线索。 ARF通过引起细胞周期停滞来响应这些提示，从而有效地减弱了这些刺激的致瘤潜力。先前的报道表明，致癌基因Ras V12 信号通过Dmp1转录因子介导的机制诱导ARF。但是，我们现在表明，在不存在 Dmp1 的情况下，通过增强现有 Arf mRNA的翻译，仍会响应Ras V12 诱导ARF蛋白。在这里，我们报告的发展中的拉斯/结节性硬化症复合体（TSC）/ mTORC1信号通路调节ARF蛋白表达，并通过新型翻译机制触发ARF介导的肿瘤抑制。通过 Tsc1 丢失导致mTORC1的过度激活导致ARF表达的显着增加，p53途径的激活以及明显的细胞周期停滞，这在 Arf 缺失后被完全逆转。在不存在 Dmp1 的情况下，由Ras V12 诱导的ARF蛋白可抑制同种异体移植模型中软琼脂的锚定非依赖性集落形成和肿瘤负荷。综上所述，我们的数据证明了ARF抑癌药对过度生长刺激作出反应以预防不必要的肿瘤形成的能力。

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