Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions.
Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions.
复制标题
DOI：
10.1371/journal.pone.0168031
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Oro AE
中科院分区：
文献类型：
--
作者：
Urman NM;Mirza A;Atwood SX;Whitson RJ;Sarin KY;Tang JY;Oro AE
Hedgehog通路是细胞生长的有效调节因子，在许多癌症（包括基底细胞癌（BCC））的发展中起着核心作用。大多数BCC由Patched受体的突变引起，导致Hedgehog途径的组成性激活。次级驱动突变促进BCC肿瘤发生，并且由于皮肤暴露于阳光导致的高突变负担而频繁发生。在这里，我们发现了融合抑制因子（SUFU）的新的二级突变，SUFU是Hedgehog通路的主要负调节因子。SUFU通常与Hedgehog转录激活因子GLI 1结合，以防止其启动Hedgehog靶基因的转录。我们对早期散发性基底细胞癌患者的肿瘤-正常配对进行了测序。这导致在SUFU中发现了9个突变，对其进行了功能研究，以确定它们是否有助于推动BCC的形成。我们的研究结果表明，四个SUFU突变不适当地激活了Hedgehog通路，这表明它们可能作为BCC发展的驱动突变。事实上，发现所有四种功能丧失的SUFU变体破坏其与GLI的结合，导致组成性途径活化。我们对这些突变的功能表征结果揭示了SUFU在Hedgehog信号传导、肿瘤进展中的作用，并突出了BCC可能出现的方式。
The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU’s role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.
登录
查看更多内容
DOI：
10.1107/s0907444913028473
发表时间：
2013-12
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Cherry AL;Finta C;Karlström M;Jin Q;Schwend T;Astorga-Wells J;Zubarev RA;Del Campo M;Criswell AR;de Sanctis D;Jovine L;Toftgård R
通讯作者：
Toftgård R
影响因子：
4.8
作者：
Dunaeva, M;Michelson, P;Toftgard, R
通讯作者：
Toftgard, R
影响因子：
3.6
作者：
So, Po-Lin;Langston, Alexander W.;Epstein, Ervin H., Jr.
通讯作者：
Epstein, Ervin H., Jr.
DOI：
10.1073/pnas.082096999
发表时间：
2002-04-16
影响因子：
11.1
作者：
Cheng, SY;Bishop, JM
通讯作者：
Bishop, JM
影响因子：
14.9
作者：
Forbes SA;Beare D;Gunasekaran P;Leung K;Bindal N;Boutselakis H;Ding M;Bamford S;Cole C;Ward S;Kok CY;Jia M;De T;Teague JW;Stratton MR;McDermott U;Campbell PJ
通讯作者：
Campbell PJ