| Description |
Chromosomal rearrangements resulting in an overexpression of a subset of ETS transcription factors (ETV1, ETV4, ETV5, and ERG) are found in over 50% of prostate cancers (Tomlins et al., 2005). ERG and ETV1 have both shared and distinct gene targets, yet overexpression of ETV1 is often found to be associated with a more aggressive form of prostate cancer (Baena et al., 2013). The mediator subunit MED25, which has been shown to interact with the N-terminus of ETV1/4/5, could be important for the initiation of transcription at ETV1-specific gene targets. I hypothesize that MED25 is able to interact with the ETV subfamily specifically, as compared to other ETS family members, through a unique interaction outside the characteristic ETS DNA-binding domain. This could lead to transcriptional activation of ETV-specific gene targets, such as androgen synthesis, in the prostate-resulting in an overall increase in androgen signaling which seems to lead towards a more aggressive form of prostate cancer. Previous studies separately showing the interaction of ETV5 and other proteins of similar structure and sequence to ETV1/4/5 with MED25 led to the design of a minimally-sized fragment of ETV4 that would not only be sufficient, but also allow maximum binding to MED25-the interaction causing structural changes likely resulting in maximal transcriptional activation. My thesis reports an interaction between MED25 and ETV4 and no interaction between MED25 and other ETS family members. I also show evidence for a novel secondary site important for binding to MED25 within ETV4. These findings could be important for regulation of transcriptional activity within the prostate, especially in developing new treatment options for this more aggressive form of cancer. |
