The RNA-binding protein QKI suppresses cancer-associated aberrant splicing.
The RNA-binding protein QKI suppresses cancer-associated aberrant splicing.
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RNA 结合蛋白 QKI 抑制癌症相关的异常剪接
DOI：
10.1371/journal.pgen.1004289
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发表时间：
2014-04
期刊：
影响因子：
4.5
通讯作者：
Hui J
中科院分区：
文献类型：
--
作者：
Zong FY;Fu X;Wei WJ;Luo YG;Heiner M;Cao LJ;Fang Z;Fang R;Lu D;Ji H;Hui J
肺癌是全球癌症相关死亡的主要原因。异常剪接与肺肿瘤的发生有关。然而，剪接调控和肺癌之间的功能联系还不是很清楚。在这里，我们发现RNA结合蛋白QKI是肺癌选择性剪接的关键调节因子。我们发现QKI在肺癌中经常下调，而且它的下调与较差的预后显著相关。QKI-5在体内外均能抑制肺癌细胞的增殖和转化。我们的结果表明，QKI-5通过与其Pre-mRNA中的两个RNA元件结合来调节Numb的选择性剪接，从而抑制细胞增殖并阻止Notch信号通路的激活。我们进一步表明，QKI-5通过选择性地与核心剪接因子SF1竞争结合到分支点序列来抑制剪接。综上所述，我们的数据揭示了QKI是肺癌剪接的关键调节因子，并提示了一种新的肿瘤抑制机制，涉及QKI介导的Notch信号通路的调节。
Lung cancer is the leading cause of cancer-related death worldwide. Aberrant splicing has been implicated in lung tumorigenesis. However, the functional links between splicing regulation and lung cancer are not well understood. Here we identify the RNA-binding protein QKI as a key regulator of alternative splicing in lung cancer. We show that QKI is frequently down-regulated in lung cancer, and its down-regulation is significantly associated with a poorer prognosis. QKI-5 inhibits the proliferation and transformation of lung cancer cells both in vitro and in vivo. Our results demonstrate that QKI-5 regulates the alternative splicing of NUMB via binding to two RNA elements in its pre-mRNA, which in turn suppresses cell proliferation and prevents the activation of the Notch signaling pathway. We further show that QKI-5 inhibits splicing by selectively competing with a core splicing factor SF1 for binding to the branchpoint sequence. Taken together, our data reveal QKI as a critical regulator of splicing in lung cancer and suggest a novel tumor suppression mechanism involving QKI-mediated regulation of the Notch signaling pathway.
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影响因子：
64.5
作者：
Cooper TA;Wan L;Dreyfuss G
通讯作者：
Dreyfuss G
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
7
作者：
Brooks, Angela N.;Yang, Li;Graveley, Brenton R.
通讯作者：
Graveley, Brenton R.
影响因子：
7.7
作者：
Grosso, Ana Rita;Martins, Sandra;Carmo-Fonseca, Maria
通讯作者：
Carmo-Fonseca, Maria
影响因子：
3.3
作者：
Doukhanine E;Gavino C;Haines JD;Almazan G;Richard S
通讯作者：
Richard S