Molecular mechanisms specific to ETS transcription factors that drive oncogenesis

项目总结/摘要 前列腺癌基因组最常见的改变是染色体重排， 在前列腺细胞中不正常表达的ETS家族转录因子的异常表达。 这些因子，包括ERG、ETV 1和ETV 4在前列腺细胞中的表达是致癌的。但 在正常前列腺中存在的许多其他ETS因子对正常功能很重要，甚至可以 成为肿瘤抑制剂。因此，为了设计靶向前列腺癌中ETS因子的疗法， 了解致癌家族成员特有的功能机制。的初步数据 本申请人的实验室支持该建议的中心假设，该建议提出所有致癌ETS 家族成员通过特定的机制激活类似的基因表达程序， 非致癌ETS蛋白。以下三个具体目标将用于确定 致癌ETS蛋白：1）确定ETS因子的共同反式激活机制， 2）识别信号通路用于调节前列腺细胞中ERG功能的机制; 和3）确定致癌ETS因子在ETS家族背景下如何在前列腺细胞中起作用。 这些目标是由强有力的初步数据指导的，包括鉴定特异性地 与致癌ETS蛋白相关，而与非致癌ETS蛋白无关。体外和体内测定 将测试这些相互作用的重要性，并将使用生物化学和 全基因组定位技术。这些研究的完成将产生第一个理解的功能 致癌ETS蛋白独特的机制，并提供重要的新的分子靶点， 预防癌症生长和进展的药理学策略。

PROJECT SUMMARY/ABSTRACT The most common alterations of the prostate cancer genome are chromosomal rearrangements that result in aberrant expression of an ETS family transcription factor that is not normally expressed in prostate cells. Expression of these factors, including ERG, ETV1, and ETV4, in prostate cells is oncogenic. However, there are many other ETS factors present in normal prostate that are important for normal functions, and can even be tumor suppressors. Thus, to devise therapies to target ETS factors in prostate cancer, it is critical to understand specific functional mechanisms specific to oncogenic family members. Preliminary data from the applicants' laboratory supports the central hypothesis of this proposal, which proposes that all oncogenic ETS family members activate a similar gene expression program through specific mechanisms that are not used by non-oncogenic ETS proteins. The following three specific aims will be used to identify specific functions of oncogenic ETS proteins: 1) Determine the common transactivation mechanism of ETS factors that drive prostate cancer; 2) Identify mechanisms used by signaling pathways to regulate ERG function in prostate cells; and 3) Determine how oncogenic ETS factors function in prostate cells within the context of the ETS family. These aims are guided by strong preliminary data including the identification of proteins that specifically associate with oncogenic ETS proteins and not with non-oncogenic ETS proteins. In vitro and in vivo assays will test the importance of these interactions, and mechanistic details will be determined using biochemical and genome-wide mapping techniques. Completion of these studies will yield the first understanding of functional mechanisms unique to oncogenic ETS proteins and provide important new molecular targets for pharmacological strategies to prevent both the growth and progression of cancer.