Negative regulation of the FOXO3a transcription factor by mTORC2 induces a pro-survival response following exposure to ultraviolet-B irradiation.
Negative regulation of the FOXO3a transcription factor by mTORC2 induces a pro-survival response following exposure to ultraviolet-B irradiation.
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DOI：
10.1016/j.cellsig.2016.03.013
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发表时间：
2016-08
影响因子：
4.8
通讯作者：
Shantz LM
中科院分区：
文献类型：
--
作者：
Feehan RP;Shantz LM
暴露于紫外线B（UVB）照射，非黑色素瘤皮肤癌（NMSC）的主要原因，激活雷帕霉素敏感的哺乳动物雷帕霉素复合物1（mTORC 1）和雷帕霉素抗性mTORC 2。我们以前曾报道，UVB诱导的角质形成细胞的生存依赖于mTORC 2，虽然具体的机制还没有很好地理解。FOXO 3a是一种重要的转录因子，参与调节细胞存活。FOXO 3 a的活性由于蛋白激酶B（AKT/PK B）激活而降低，该蛋白激酶B激活位于mTORC 2的下游;然而，FOXO 3 a在UVB诱导的细胞凋亡过程中的具体功能尚不清楚。在这项研究中，我们建立了野生型mTORC 2活性的细胞，FOXO 3a是迅速磷酸化，以响应UVB和隔离在细胞质中。相反，mTORC 2的缺失导致FOXO 3a定位于细胞核，并使细胞对UVB诱导的细胞凋亡敏感。此外，通过敲低FOXO 3a来挽救这种致敏作用。总之，这些研究提供了强有力的证据表明，mTORC 2的抑制增强UVB诱导的细胞凋亡中的FOXO 3a依赖的方式，并表明FOXO 3a激活mTORC 2抑制剂可能是一个有价值的化学预防NMSC的目标。
Exposure to ultraviolet-B (UVB) irradiation, the principal cause of non-melanoma skin cancer (NMSC), activates both the rapamycin-sensitive mammalian target of rapamycin complex 1 (mTORC1) and the rapamycin-resistant mTORC2. We have previously reported that UVB-induced keratinocyte survival is dependent on mTORC2, though the specific mechanism is not well understood. FOXO3a is an important transcription factor involved in regulating cell survival. The activity of FOXO3a is reduced as a result of protein kinase B (AKT/PKB) activation, which is downstream of mTORC2; however, the specific function of FOXO3a during UVB-induced apoptosis is unclear. In this study, we establish that in cells with wild-type mTORC2 activity, FOXO3a is quickly phosphorylated in response to UVB and sequestered in the cytoplasm. In contrast, loss of mTORC2 causes FOXO3a to be localized to the nucleus and sensitizes cells to UVB-induced apoptosis. Furthermore, this sensitization is rescued by knockdown of FOXO3a. Taken together, these studies provide strong evidence that inhibition of mTORC2 enhances UVB-induced apoptosis in a FOXO3a-dependent manner, and suggest that FOXO3a activation by mTORC2 inhibitors may be a valuable chemopreventive target in NMSC.