Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors.
Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors.
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DOI：
10.15252/embj.201489213
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发表时间：
2015-01-13
期刊：
影响因子：
--
通讯作者：
Di Marcotullio L
中科院分区：
文献类型：
--
作者：
Infante P;Mori M;Alfonsi R;Ghirga F;Aiello F;Toscano S;Ingallina C;Siler M;Cucchi D;Po A;Miele E;D'Amico D;Canettieri G;De Smaele E;Ferretti E;Screpanti I;Uccello Barretta G;Botta M;Botta B;Gulino A;Di Marcotullio L
Hedgehog信号传导对于组织发育和干性是必不可少的，并且在许多肿瘤中已经观察到其失调。Hedgehog信号传导的异常激活是通路组分或其他Smo依赖性或独立机制的基因突变的结果，所有这些都触发了下游效应物Gli 1。由于这个原因，了解Gli 1介导的转录机制不清楚，可以识别在下游水平阻断该途径的新分子，这是肿瘤生物学的一个关键目标。在这里，我们澄清的结构要求的途径效应Gli 1结合到DNA和确定Glabrescione B作为第一个小分子结合到Gli 1锌指和损害Gli 1的活性，通过干扰其与DNA的相互作用。值得注意的是，由于Glabrescione B对Gli 1活性具有强大的抑制作用，因此在体外和体内抑制Hedgehog依赖性肿瘤细胞的生长以及肿瘤源性干细胞的自我更新能力和克隆形成。Gli 1/DNA相互作用的结构要求的鉴定突出了它们与Gli信号的药理学干扰的相关性。
Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
56.9
作者：
Berman, DM;Karhadkar, SS;Beachy, PA
通讯作者：
Beachy, PA
影响因子：
82.9
作者：
通讯作者：
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影响因子：
11.1
作者：
Eberl, Markus;Klingler, Stefan;Mangelberger, Doris;Loipetzberger, Andrea;Damhofer, Helene;Zoidl, Kerstin;Schnidar, Harald;Hache, Hendrik;Bauer, Hans-Christian;Solca, Flavio;Hauser-Kronberger, Cornelia;Ermilov, Alexandre N.;Verhaegen, Monique E.;Bichakjian, Christopher K.;Dlugosz, Andrzej A.;Nietfeld, Wilfried;Sibilia, Maria;Lehrach, Hans;Wierling, Christoph;Aberger, Fritz
通讯作者：
Aberger, Fritz
DOI：
10.1073/pnas.0907134106
发表时间：
2009-08-18
影响因子：
11.1
作者：
Hyman, Joel M.;Firestone, Ari J.;Chen, James K.
通讯作者：
Chen, James K.