Non-canonical activation of GLI transcription factors -: Implications for targeted anti-cancer therapy
Non-canonical activation of GLI transcription factors -: Implications for targeted anti-cancer therapy
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DOI：
10.4161/cc.6.20.4808
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发表时间：
2007-10-15
期刊：
影响因子：
4.3
通讯作者：
Toftgard, Rune
中科院分区：
文献类型：
--
作者：
Lauth, Matthias;Toftgard, Rune
GLI转录因子构成Hedgehog（HH）信号通路的最终效应子。在许多肿瘤中，如胰腺、前列腺、皮肤或肺的肿瘤，GLI蛋白的异位激活与肿瘤发生有关。在其中几种情况下，HH配体或受体诱导的信号传导（经典HH信号传导）被发现是GLI激活的潜在原因。最近的证据指向额外的，非经典的，GLI激活机制。在这里，我们回顾了两个HH无关的信号通路（RAS和转化生长因子β）的HH通路下游的信号组件平滑的串扰的研究结果。两种途径刺激和/或诱导GLI 1和GLI 2活性，而不依赖于HH配体的存在。我们还讨论了这些串扰机制对肿瘤细胞转移的假定作用。GLI转录因子作为众多信号输入的整合平台的新兴图景对于理解肿瘤发展具有重要意义，并主张在当前药物开发计划的设计中包括作用于受体水平下游的靶标。
GLI transcription factors constitute the final effectors of the Hedgehog (HH) signaling pathway. In many tumors, such as those of the pancreas, prostate, skin or lung, ectopic activation of GLI proteins has been linked to tumorigenesis. In several of these cases, HH ligand- or receptor-induced signaling (canonical HH signaling) was found to be the cause underlying GLI activation. Recent evidence points towards additional, non-canonical, mechanisms of GLI activation. Here we review findings on the crosstalk of two HH-unrelated signaling pathways (RAS and Transforming growth factor beta) to the HH pathway downstream of the signaling component Smoothened. Both pathways stimulate and/or induce GLI1 and GLI2 activity independent of the presence of HH ligands. We also discuss the putative roles of these crosstalk mechanisms for tumor cell metastasis. The emerging picture of GLI transcription factors as an integrative platform of numerous signaling inputs has important implications for the understanding of tumor development and argues for inclusion of targets acting downstream of the receptor level in the design of current drug development programs.