The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI.
The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI.
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DOI：
10.1016/j.celrep.2017.08.048
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发表时间：
2017-09-05
期刊：
影响因子：
8.8
通讯作者：
Dotto GP
中科院分区：
文献类型：
--
作者：
Goruppi S;Procopio MG;Jo S;Clocchiatti A;Neel V;Dotto GP
激活癌症相关成纤维细胞（CAF）的信号通路之间的联系仍有待确定。与自噬相关的代谢改变也与CAF激活有关。CSL/RBPJ是一种介导Notch信号传导的转录阻遏物，抑制导致基质衰老和CAF活化的基因表达程序。Gli信号转导失调也有助于CAF转化。在这里，我们报告说，受损的CSL功能依赖于Gli激活的人真皮成纤维细胞转化为CAFs，从细胞衰老分开。CSL减少上调Ulk 3激酶的表达，Ulk 3激酶结合并激活Gli 2。增加的Ulk 3也诱导自噬，这与Gli和CAF激活无关。Ulk 3上调发生在几种肿瘤类型的CAF中，并且Ulk 3沉默抑制这些细胞的肿瘤增强特性。因此，Ulk 3连接了参与CAF转化的两个关键信号通路，并且是基质聚焦抗癌干预的有吸引力的靶标
The connection between signaling pathways activating cancer associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses gene expression program(s) leading to stromal senescence and CAF activation. Deregulated Gli signaling can also contribute to CAF conversion. Here we report that compromised CSL function depends on Gli activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL up-regulates the expression of the Ulk3 kinase, which binds and activates Gli2. Increased Ulk3 also induces autophagy, which is unlinked from Gli and CAF activation. Ulk3 up-regulation occurs in CAFs of several tumor types and Ulk3 silencing suppresses the tumor enhancing properties of these cells. Thus, Ulk3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
--
作者：
Barth JM;Köhler K
通讯作者：
Köhler K
影响因子：
64.5
作者：
Hu B;Castillo E;Harewood L;Ostano P;Reymond A;Dummer R;Raffoul W;Hoetzenecker W;Hofbauer GF;Dotto GP
通讯作者：
Dotto GP
影响因子：
3.3
作者：
Kong DK;Georgescu SP;Cano C;Aronovitz MJ;Iovanna JL;Patten RD;Kyriakis JM;Goruppi S
通讯作者：
Goruppi S
影响因子：
11.5
作者：
Ashida, Shingo;Orloff, Mohammed S.;Eng, Charis
通讯作者：
Eng, Charis