RNAi screens in mice identify physiological regulators of oncogenic growth.
RNAi screens in mice identify physiological regulators of oncogenic growth.
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作者：
组织生长是细胞内在能力及其与周围环境相互作用的多方面结果。破译这些复杂性对于理解人类发育和肿瘤发生至关重要。在这里，我们通过在小鼠身上进行第一次全基因组RNAi介导性筛选来解决这个问题。我们的屏幕聚焦于皮肤发育和致癌(HrasG12V诱导的)增殖，揭示了胚胎表皮生长的新的和预期的调节因素。在致癌屏幕上最热门的是Mllt6和Wnt效应器β-catenin；它们维持依赖于HrasG12V的过度增殖。我们还揭示了β-连环蛋白作为一种意想不到的正常表皮生长的拮抗剂，通过WNT独立的细胞间黏附发挥作用。最后，我们记录了与小鼠和人类癌症的生理相关性，从而建立了活体哺乳动物全基因组研究的可行性，以解剖组织发育和肿瘤发生。通过记录一些致癌生长调节因子，我们为未来对其他HITS的研究铺平了道路，并提高了为癌症治疗发现新靶点的希望。
Tissue growth is the multifaceted outcome of a cell’s intrinsic capabilities and its interactions with the surrounding environment. Decoding these complexities is essential for understanding human development and tumorigenesis. Here, we tackle this problem by carrying out the first genome-wide RNAi-mediated screens in mice. Focusing on skin development and oncogenic (HrasG12V-induced) hyperplasia, our screens uncover novel as well as anticipated regulators of embryonic epidermal growth. Among top oncogenic screen hits are Mllt6 and the Wnt effector β-catenin; they maintain HrasG12V-dependent hyperproliferation. We also expose β-catenin as an unanticipated antagonist of normal epidermal growth, functioning through Wnt-independent intercellular adhesion. Finally, we document physiological relevance to mouse and human cancers, thereby establishing the feasibility of in vivo mammalian genome-wide investigations to dissect tissue development and tumorigenesis. By documenting some oncogenic growth regulators, we pave the way for future investigations of other hits and raise promise for unearthing new targets for cancer therapies.
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DOI：
10.1007/978-1-59745-060-7_14
发表时间：
2009
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1083/jcb.201004104
发表时间：
2010-05-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Linkert M;Rueden CT;Allan C;Burel JM;Moore W;Patterson A;Loranger B;Moore J;Neves C;Macdonald D;Tarkowska A;Sticco C;Hill E;Rossner M;Eliceiri KW;Swedlow JR
通讯作者：
Swedlow JR
DOI：
10.1073/pnas.1121312110
发表时间：
2013-01-22
影响因子：
11.1
作者：
Kandyba, Eve;Leung, Yvonne;Kobielak, Krzysztof
通讯作者：
Kobielak, Krzysztof
影响因子：
11.2
作者：
Babij, Carol;Zhang, Yihong;Dussault, Isabelle
通讯作者：
Dussault, Isabelle
影响因子：
5.2
作者：
Miyata, Yasuhiko;Liu, Yan;Jankovic, Vladimir;Sashida, Goro;Lee, Jennifer May;Shieh, Jae-Hung;Naoe, Tomoki;Moore, Malcolm;Nimer, Stephen D.
通讯作者：
Nimer, Stephen D.