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000129046 0247_ $$2doi$$a10.1158/0008-5472.CAN-16-1547
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000129046 0247_ $$2ISSN$$a0099-7013
000129046 0247_ $$2ISSN$$a0099-7374
000129046 0247_ $$2ISSN$$a1538-7445
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000129046 037__ $$aDKFZ-2017-05051
000129046 041__ $$aeng
000129046 082__ $$a610
000129046 1001_ $$aLi, Peng$$b0
000129046 245__ $$aNestin Mediates Hedgehog Pathway Tumorigenesis.
000129046 260__ $$aPhiladelphia, Pa.$$bAACR$$c2016
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000129046 520__ $$aThe intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here, we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation, resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Cancer Res; 76(18); 5573-83. ©2016 AACR.
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000129046 650_7 $$2NLM Chemicals$$aGli3 protein, mouse
000129046 650_7 $$2NLM Chemicals$$aHedgehog Proteins
000129046 650_7 $$2NLM Chemicals$$aKruppel-Like Transcription Factors
000129046 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000129046 650_7 $$2NLM Chemicals$$aNes protein, mouse
000129046 650_7 $$2NLM Chemicals$$aNestin
000129046 7001_ $$aLee, Eric H$$b1
000129046 7001_ $$aDu, Fang$$b2
000129046 7001_ $$aGordon, Renata E$$b3
000129046 7001_ $$aYuelling, Larra W$$b4
000129046 7001_ $$aLiu, Yongqiang$$b5
000129046 7001_ $$aNg, Jessica M Y$$b6
000129046 7001_ $$aZhang, Hao$$b7
000129046 7001_ $$aWu, Jinhua$$b8
000129046 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b9$$udkfz
000129046 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b10$$udkfz
000129046 7001_ $$aCurran, Tom$$b11
000129046 7001_ $$aYang, Zeng-Jie$$b12
000129046 773__ $$0PERI:(DE-600)2036785-5$$a10.1158/0008-5472.CAN-16-1547$$gVol. 76, no. 18, p. 5573 - 5583$$n18$$p5573 - 5583$$tCancer research$$v76$$x1538-7445$$y2016
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