Abstract 3090: Oncogenic ETS transcription factors bind ETS/AP-1 sequences and activate a RAS/MAPK gene expression program in the absence of MAPK activation
2012
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL
Deciphering the mechanism of transcription factor function in both normal and disease states requires understanding how these proteins are targeted to specific genomic binding sites, influence transcription, and how these functions are modified by signaling pathways. However, overlapping functions among the thousands of transcription factors encoded by the human genome have made it difficult to assign specific mechanisms. Approximately 50% of prostate cancers have chromosomal rearrangements resulting in the over-expression any one of four ETS-family transcription factors. It is not known why these four ETS family members are associated with prostate cancers, while the other 24 human ETS genes are not. We found that the four oncogenic ETS family members have a specific role in prostate cell migration that does not extend to other family members. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq), this specific biological function was matched to a specific set of genomic targets highlighted by the presence of both ETS and AP-1 binding sequences. ETS/AP-1 binding sequences are prototypical RAS-responsive elements where a MAPK can phosphorylate ETS proteins increasing transcriptional activation. We found that oncogenic ETS proteins could activate a RAS/MAPK transcriptional program when the MAPK pathway was inactive. These findings indicate that a specific function of ETS proteins over-expressed in prostate cancer is the activation of a RAS/MAPK gene expression program in the absence of activating mutations in the RAS/MAPK signaling pathway. We propose that this ETS/AP-1 regulated, RAS-responsive, transcriptional network will also play a critical role in other cancers that do not over-express an ETS protein, but have activating mutations in the RAS/MAPK pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3090. doi:1538-7445.AM2012-3090
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