Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells.
Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells.
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DOI：
10.18632/oncotarget.2319
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发表时间：
2014-09-30
期刊：
影响因子：
--
通讯作者：
Platanias LC
中科院分区：
文献类型：
--
作者：
Eckerdt F;Beauchamp E;Bell J;Iqbal A;Su B;Fukunaga R;Lulla RR;Goldman S;Platanias LC
mTOR通路控制有丝分裂蛋白的mRNA翻译，是恶性细胞代谢的中心调节因子。恶性细胞耐药的发展是mTOR抑制剂作用的限制因素，但这种耐药的机制尚不清楚。我们提供的证据表明，雷帕霉素抑制mTORC1导致恶性髓母细胞瘤细胞参与负反馈调节回路，涉及真核翻译起始因子eIF4E的磷酸化。这种eIF4E磷酸化是Mnk2介导的，但与mnk1无关，并作为成神经管细胞瘤细胞的存活机制。药理靶向Mnk1/2或sirna介导的敲低Mnk2使髓母细胞瘤细胞对mTOR抑制敏感，促进恶性细胞增殖和不依赖锚定生长的抑制。总之，这些发现为髓母细胞瘤细胞中存在mnk2控制的反馈回路提供了证据，该反馈回路解释了mTOR抑制剂的耐药性，并提高了mTOR和Mnk抑制剂联合治疗髓母细胞瘤的可能性。
The mTOR pathway controls mRNA translation of mitogenic proteins and is a central regulator of metabolism in malignant cells. Development of malignant cell resistance is a limiting factor to the effects of mTOR inhibitors, but the mechanisms accounting for such resistance are not well understood. We provide evidence that mTORC1 inhibition by rapamycin results in engagement of a negative feedback regulatory loop in malignant medulloblastoma cells, involving phosphorylation of the eukaryotic translation-initiation factor eIF4E. This eIF4E phosphorylation is Mnk2- mediated, but Mnk1-independent, and acts as a survival mechanism for medulloblastoma cells. Pharmacological targeting of Mnk1/2 or siRNA-mediated knockdown of Mnk2 sensitizes medulloblastoma cells to mTOR inhibition and promotes suppression of malignant cell proliferation and anchorage-independent growth. Altogether, these findings provide evidence for the existence of a Mnk2-controlled feedback loop in medulloblastoma cells that accounts for resistance to mTOR inhibitors, and raise the potential for combination treatments of mTOR and Mnk inhibitors for the treatment of medulloblastoma.
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髓母细胞瘤外观测序发现亚型特异性体细胞突变。
影响因子：
64.8
作者：
Pugh, Trevor J.;Weeraratne, Shyamal Dilhan;Archer, Tenley C.;Krummel, Daniel A. Pomeranz;Auclair, Daniel;Bochicchio, James;Carneiro, Mauricio O.;Carter, Scott L.;Cibulskis, Kristian;Erlich, Rachel L.;Greulich, Heidi;Lawrence, Michael S.;Lennon, Niall J.;McKenna, Aaron;Meldrim, James;Ramos, Alex H.;Ross, Michael G.;Russ, Carsten;Shefler, Erica;Sivachenko, Andrey;Sogoloff, Brian;Stojanov, Petar;Tamayo, Pablo;Mesirov, Jill P.;Amani, Vladimir;Teider, Natalia;Sengupta, Soma;Francois, Jessica Pierre;Northcott, Paul A.;Taylor, Michael D.;Yu, Furong;Crabtree, Gerald R.;Kautzman, Amanda G.;Gabriel, Stacey B.;Getz, Gad;Jaeger, Natalie;Jones, David T. W.;Lichter, Peter;Pfister, Stefan M.;Roberts, Thomas M.;Meyerson, Matthew;Pomeroy, Scott L.;Cho, Yoon-Jae
通讯作者：
Cho, Yoon-Jae
影响因子：
20.3
作者：
Altman, Jessica K.;Szilard, Amy;Platanias, Leonidas C.
通讯作者：
Platanias, Leonidas C.
DOI：
10.1073/pnas.0900562106
发表时间：
2009-07-21
影响因子：
11.1
作者：
Joshi, Sonali;Kaur, Surinder;Platanias, Leonidas C.
通讯作者：
Platanias, Leonidas C.
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing
影响因子：
5.3
作者：
Julien, Louis-Andre;Carriere, Audrey;Roux, Philippe P.
通讯作者：
Roux, Philippe P.