A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma.
A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma.
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作者：
控制蛋白质合成的因子表达失调与许多癌症的预后不良有关，但其潜在机制尚未明确。弥漫性大B细胞淋巴瘤（DLBCL）translatome的分析显示，选择性上调的mRNA编码抗凋亡和DNA修复蛋白。我们表明，这些蛋白质在DLBCL中的合成增强是由相应mRNA的5′-非翻译区结构通常施加的抑制的缓解介导的。这一过程是由通过哺乳动物雷帕霉素靶点的信号传导驱动的，导致真核起始因子（eIF）4 B复合物（eIF 4 B）的合成增加，eIF 4 B是RNA解旋酶eIF 4A的已知激活剂。单独降低eIF 4 B表达足以减少与增强的肿瘤细胞存活相关的蛋白质（即DAXX、BCL 2和ERCC 5）的合成。重要的是，eIF 4 B驱动的这些关键生存蛋白的表达与患者结局直接相关，并且eIF 4 B、DAXX和ERCC 5被鉴定为DLBCL中生存不良的新预后标志物。我们的工作提供了新的见解的机制，促进癌症的翻译机器驱动淋巴瘤。
Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5′-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis.
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影响因子：
3.7
作者：
Lorenz WA;Clote P
通讯作者：
Clote P
胰腺神经内分泌肿瘤中经常改变DAXX/ATRX，MEN1和MTOR途径基因。
DOI：
10.1126/science.1200609
发表时间：
2011-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jiao Y;Shi C;Edil BH;de Wilde RF;Klimstra DS;Maitra A;Schulick RD;Tang LH;Wolfgang CL;Choti MA;Velculescu VE;Diaz LA Jr;Vogelstein B;Kinzler KW;Hruban RH;Papadopoulos N
通讯作者：
Papadopoulos N
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：
4.4
作者：
Park EH;Zhang F;Warringer J;Sunnerhagen P;Hinnebusch AG
通讯作者：
Hinnebusch AG
影响因子：
64.8
作者：
Alizadeh, AA;Eisen, MB;Staudt, LM
通讯作者：
Staudt, LM