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Molecular mechanisms specific to ETS transcription factors that drive oncogenesis

驱动肿瘤发生的 ETS 转录因子特有的分子机制

基本信息

批准号：
10206043
负责人：
Peter Celestine Hollenhorst
金额：
$ 46.45万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206043
关键词：
Binding Sites Biochemical Biological Assay Biological Process Cancer Etiology Cancer Patient Cell physiology Cells Chromosomal Rearrangement Complex Data Development ETS Family Protein ETV1 gene ETV4 gene EZH2 gene Event Family Family member Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Growth Human In Vitro Laboratories Lead Length Lesion MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of prostate Microsatellite Repeats Molecular Molecular Target Mutation N-terminal Oncogenes Oncogenic PI3K/AKT Pathway interactions Patients Pharmacology Phosphorylation Phosphorylation Site Polycomb Prostate Prostate Adenocarcinoma Prostate Cancer therapy Prostatic Neoplasms Proteins Proto-Oncogene Proteins c-akt Publishing RNA-Binding Protein EWS Regulation Regulatory Element Repression Role Signal Pathway Signal Transduction TMPRSS2 gene Techniques Testing Therapeutic Transactivation Transcription Factor AP-1 Tumor Suppressor Proteins base cancer genome cancer therapy cell motility genetic corepressor genome-wide improved in vivo inhibitor/antagonist mouse model mutational status non-oncogenic novel novel strategies precision medicine prevent programs prostate carcinogenesis protein function protein protein interaction therapeutic development transcription factor tumor tumor progression tumorigenesis

项目摘要

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.

项目总结/文摘