Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling.
Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling.
复制标题
DOI：
10.1126/scisignal.2001225
复制
发表时间：
2011-01-25
影响因子：
7.3
通讯作者：
Lum L
中科院分区：
文献类型：
--
作者：
Jacob LS;Wu X;Dodge ME;Fan CW;Kulak O;Chen B;Tang W;Wang B;Amatruda JF;Lum L
Hedgehog（Hh）和Wnt信号转导途径是胚胎发生和组织更新的主要调节剂，并且代表抗癌治疗靶点。在小鼠培养细胞中使用全基因组RNA干扰筛选，我们建立了这些信号通路与发育畸形，过早组织变性疾病和癌症相关基因之间的先前未知的关联。我们确定了多任务激酶Stk11（也称为Lkb1）在两种途径中的功能，Stk11是一种与肺癌和宫颈癌有关的肿瘤抑制因子。我们发现Stk11的丢失导致初级纤毛的解体，初级纤毛是Hh通路组分的细胞组织中心，从而抑制Hh信号传导。Stk11的缺失也通过Wnt途径诱导异常信号传导。针对Wnt酰基转移酶Porcupine或通过抑制微管蛋白脱乙酰酶HDAC 6（组蛋白脱乙酰酶6）恢复初级纤毛长度的化学物质可以对抗Stk 11丢失导致的异常途径活动。我们的研究表明，Stk11是Hh和Wnt通路的关键介质，我们的方法提供了一个平台，以支持靶向治疗策略的发展。
The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies.
登录
查看更多内容
影响因子：
7.3
作者：
Evangelista, Marie;Lim, Tze Yang;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
56.9
作者：
Rohatgi, Rajat;Milenkovic, Ljiljana;Scott, Matthew P.
通讯作者：
Scott, Matthew P.
影响因子：
30.8
作者：
Maw, MA;Kennedy, B;Denton, MJ
通讯作者：
Denton, MJ
影响因子：
11.8
作者：
Jiang J;Hui CC
通讯作者：
Hui CC
影响因子：
14.8
作者：
Chen, Baozhi;Dodge, Michael E.;Tang, Wei;Lu, Jianming;Ma, Zhiqiang;Fan, Chih-Wei;Wei, Shuguang;Hao, Wayne;Kilgore, Jessica;Williams, Noelle S.;Roth, Michael G.;Amatruda, James F.;Chen, Chuo;Lum, Lawrence
通讯作者：
Lum, Lawrence