Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival.
Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival.
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DOI：
10.1158/1940-6207.capr-12-0272-t
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发表时间：
2012-12
期刊：
影响因子：
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通讯作者：
Shantz LM
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文献类型：
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作者：
Carr TD;DiGiovanni J;Lynch CJ;Shantz LM
紫外线（UV）辐射是发展皮肤癌的主要危险因素，皮肤癌是世界上最普遍的癌症。一些研究表明，哺乳动物雷帕霉素靶蛋白（mTOR）信号被UVB激活，并可能在皮肤肿瘤发生中发挥重要作用。mTOR存在于两种功能和组成不同的蛋白质复合物中：雷帕霉素敏感的mTOR复合物1（mTORC 1）和雷帕霉素抗性的mTOR复合物2（mTORC 2）。这些研究的目的是研究两种mTOR复合物在皮肤中UVB介导的增殖和凋亡中的作用。我们利用雷帕霉素，一种mTORC 1的药理学抑制剂，和一种诱导型mTOR缺陷（K5-CreERT 2;mTORfl/fl）小鼠模型，该模型允许在用4-羟基他莫昔芬（4 OHT）局部治疗后表皮特异性破坏mTOR。雷帕霉素阻断UVB诱导的S6 K磷酸化，mTORC 1的下游目标，并显着减少UVB刺激的表皮增殖和细胞周期进程，但对细胞死亡没有影响。相比之下，mTOR缺失，减弱UVB诱导的S6 K和mTORC 2靶AKTSer 473的磷酸化，除了减少UVB照射后的过度增殖外，还显著增加了体内和角质形成细胞培养物中的凋亡。mTORC 2在UVB诱导的促存活信号传导中的作用在Rictor-/- MEFs中得到验证，Rictor-/-MEFs缺乏功能性mTORC 2并且比对照对UVB诱导的细胞凋亡更敏感。这些研究表明mTORC 1和mTORC 2在控制皮肤增殖和凋亡中发挥独特但互补的作用。我们的研究结果强调了两种mTOR复合物在介导角质形成细胞中UVB诱导的信号传导中的重要性，并为皮肤癌的发病机制提供了新的见解。
Ultraviolet (UV) radiation is the major risk factor for developing skin cancer, the most prevalent cancer worldwide. Several studies indicate mammalian target of rapamycin (mTOR) signaling is activated by UVB and may play an important role in skin tumorigenesis. mTOR exists in two functionally and compositionally distinct protein complexes: the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-resistant mTOR complex 2 (mTORC2). The purpose of these studies was to investigate the roles of the two mTOR complexes in UVB-mediated proliferation and apoptosis in the skin. We utilized rapamycin, a pharmacological inhibitor of mTORC1, and an inducible mTOR-deficient (K5-CreERT2;mTORfl/fl) mouse model that allows epidermal-specific disruption of mTOR following topical treatment with 4-hydroxytamoxifen (4OHT). Rapamycin blocked UVB-induced phosphorylation of S6K, the downstream target of mTORC1, and significantly reduced UVB-stimulated epidermal proliferation and cell cycle progression, but had no effect on cell death. In contrast, mTOR deletion, which attenuated UVB-induced phosphorylation of both S6K and the mTORC2 target AKTSer473, significantly increased apoptosis both in vivo and in keratinocyte cultures, in addition to reducing hyperproliferation following UVB irradiation. The role of mTORC2 in UVB-induced pro-survival signaling was verified in Rictor-/- MEFs, which lack functional mTORC2 and were more sensitive to UVB-induced apoptosis than controls. These studies show that mTORC1 and mTORC2 play unique but complementary roles in controlling proliferation and apoptosis in the skin. Our findings underscore the importance of both mTOR complexes in mediating UVB-induced signaling in keratinocytes and provide new insight into the pathogenesis of skin cancer.