Rheb1-Independent Activation of mTORC1 in Mammary Tumors Occurs through Activating Mutations in mTOR.
Rheb1-Independent Activation of mTORC1 in Mammary Tumors Occurs through Activating Mutations in mTOR.
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DOI：
10.1016/j.celrep.2020.107571
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发表时间：
2020-04
期刊：
影响因子：
8.8
通讯作者：
Bin Xiao;D. Zuo;Alison Hirukawa;R. Cardiff;R. Lamb;N. Sonenberg;W. Muller
中科院分区：
文献类型：
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作者：
Bin Xiao;D. Zuo;Alison Hirukawa;R. Cardiff;R. Lamb;N. Sonenberg;W. Muller
雷帕霉素复合物1（mTORC1）的机制目标是一个主调制器的细胞生长，其异常调节在乳腺癌中反复记录。虽然小的GTdR heb 1是mTORC 1的典型激活剂，但也有报道称mTORC 1激活的Rheb 1独立机制尚未完全理解。采用多种转基因小鼠乳腺癌模型，我们报告说，消融Rheb 1显着阻碍乳腺肿瘤的发生。在没有Rheb 1的情况下，肿瘤起始的阻断可以通过Mtor中的多个独立突变来克服，以允许mTORC 1的Rheb 1独立再激活。我们进一步证明了mTOR激酶对于肿瘤的发生是不可缺少的，因为mTOR的基因消融消除了乳腺肿瘤的发生。总的来说，我们的研究结果表明，mTORC1激活是必不可少的乳腺肿瘤的启动和肿瘤获得mTORC1激活的替代机制。
Mechanistic target of rapamycin complex 1 (mTORC1) is a master modulator of cellular growth, and its aberrant regulation is recurrently documented within breast cancer. While the small GTPase Rheb1 is the canonical activator of mTORC1, Rheb1-independent mechanisms of mTORC1 activation have also been reported but have not been fully understood. Employing multiple transgenic mouse models of breast cancer, we report that ablation of Rheb1 significantly impedes mammary tumorigenesis. In the absence of Rheb1, a block in tumor initiation can be overcome by multiple independent mutations inMtorto allow Rheb1-independent reactivation of mTORC1. We further demonstrate that the mTOR kinase is indispensable for tumor initiation as the genetic ablation of mTOR abolishes mammary tumorigenesis. Collectively, our findings demonstrate that mTORC1 activation is indispensable for mammary tumor initiation and that tumors acquire alternative mechanisms of mTORC1 activation.