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题目:: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.
作者:: Pfister(Stefan),Janzarik(Wibke G),Remke(Marc),Ernst(Aurélie),Werft(Wiebke),Becker(Natalia),Toedt(Grischa),Wittmann(Andrea),Kratz(Christian),Olbrich(Heike),Ahmadi(Rezvan),Thieme(Barbara),Joos(Stefan),Radlwimmer(Bernhard),Kulozik(Andreas),Pietsch(Torsten),Herold-Mende(Christel),Gnekow(Astrid),Reifenberger(Guido),Korshunov(Andrey),Scheurlen(Wolfram),Omran(Heymut),Lichter(Peter)
状态:: 发布时间2008-05-02 , 更新时间 2014-09-03
期刊:: J Clin Invest
摘要:: The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.
语言:: eng
DOI:

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