mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3.
mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3.
复制标题
作者：
最近在结节性硬化症（TSC）中使用雷帕霉素类似物的临床试验显示典型血管化肿瘤（包括血管平滑肌脂肪瘤（AML）和室管膜下巨细胞星形细胞瘤（SEGA））的体积消退。通过阻断雷帕霉素复合物1（mTORC 1）信号传导的机制/哺乳动物靶点，雷帕霉素的疗效可能部分通过抑制缺氧诱导因子（HIF）和血管内皮生长因子（VEGF）而发生。我们发现，雷帕霉素降低了Tsc 2 +/−小鼠模型肾囊腺瘤细胞中HIF-1α蛋白水平，并在较小程度上降低了VEGF-A水平。我们确定mTORC 1通过增强HIF-1α mRNA的转录来驱动HIF-1α蛋白的积累，这一过程可通过抑制或敲低信号转导和转录激活因子3（STAT 3）来阻断。此外，我们证明了在缺氧期间，STAT 3被mTORC 1直接磷酸化Ser 727，促进HIF-1α mRNA的转录。mTORC 1还通过协同调节起始因子4 E结合蛋白1（4 E-BP 1）和核糖体蛋白S6激酶-1（S6 K1）在翻译水平上调节HIF-1α的合成，而HIF-1α的降解不受影响。因此，我们认为mTORC 1通过4 E-BP 1/eIF 4 E、S6 K1和STAT 3以多方面的方式驱动HIF-1α的合成。有趣的是，我们观察到HIF-1α蛋白水平和VEGF-A表达之间的脱节。虽然S6 K1和4 E-BP 1都调节HIF-1α的翻译，但VEGF-A主要受4 E-BP 1/eIF 4 E的控制。抑制S6 K1可降低HIF-1α表达，但不降低VEGF-A表达，表明mTORC 1通过HIF-1α依赖性和非依赖性机制介导VEGF-A表达。我们的工作对血管化肿瘤的治疗具有重要意义，其中mTORC 1通过多种信号传导机制作为STAT 3，HIF-1α，VEGF-A和血管生成的中心介导物。
Recent clinical trials using rapalogues in tuberous sclerosis complex (TSC) show regression in volume of typically vascularised tumours including angiomyolipomas (AMLs) and sub-ependymal giant cell astrocytomas (SEGAs). By blocking mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signalling, rapalogue efficacy is likely to occur in part through suppression of hypoxia inducible factors (HIFs) and vascular endothelial growth factors (VEGFs). We show that rapamycin reduces HIF-1α protein levels, and to a lesser extent VEGF-A levels, in renal cystadenoma cells in a Tsc2+/− mouse model. We establish that mTORC1 drives HIF-1α protein accumulation through enhanced transcription of HIF-1α mRNA, a process that is blocked by either inhibition or knockdown of signal transducer and activation of transcription 3 (STAT3). Furthermore, we demonstrate that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription. mTORC1 also regulates HIF-1α synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whilst HIF-1α degradation remains unaffected. We therefore propose that mTORC1 drives HIF-1α synthesis in a multi-faceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observe a disconnect between HIF-1α protein levels and VEGF-A expression. While both S6K1 and 4E-BP1 regulate HIF-1α translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1α but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1α-dependent and -independent mechanisms. Our work has important implications for the treatment of vascularised tumours, where mTORC1 acts as a central mediator of STAT3, HIF-1α, VEGF-A and angiogenesis via multiple signalling mechanisms.
登录
查看更多内容
影响因子：
4.8
作者：
Isaacs, JS;Jung, YJ;Neckers, LM
通讯作者：
Neckers, LM
DOI：
10.1126/science.1236566
发表时间：
2013-07-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kang SA;Pacold ME;Cervantes CL;Lim D;Lou HJ;Ottina K;Gray NS;Turk BE;Yaffe MB;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.8
作者：
Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide
通讯作者：
Ruggero, Davide
影响因子：
16
作者：
Düvel K;Yecies JL;Menon S;Raman P;Lipovsky AI;Souza AL;Triantafellow E;Ma Q;Gorski R;Cleaver S;Vander Heiden MG;MacKeigan JP;Finan PM;Clish CB;Murphy LO;Manning BD
通讯作者：
Manning BD
影响因子：
7.5
作者：
Dazert, Eva;Hall, Michael N.
通讯作者：
Hall, Michael N.