Defining the Regulation of Telomerase Through Identification of Mammary- Specific Telomerase Interacting Proteins; Final rept. 1 Jun 2004-31 May 2007

摘要

Telomerase activity is associated with over 90% of human breast cancers and is necessary for continued tumor cell growth, making it an ideal target for inhibition therapy. However, pharmacologic inhibitors of telomerase have not been as effective as expected. As such, our objective here is to identify novel telomerase interacting proteins and define their functional relationship to telomerase in order to provide additional targets for telomerase inhibition in breast cancer. In addition to the results that we reported in previous annual reports concerning telomere binding proteins and chaperone interactions, we have found that telomerase is a modified protein, capable of being ubiquinated and sumolylated and is able to be degraded via both nuclear and cytoplasmic mechanisms. We show that inhibition of the Hsp90 chaperone results in telomerase degradation in the nucleus, but association of wild-type telomerase with a dominant-negative version results in cytoplasmic degradation. We show that telomerase is associated with the proteosome in both the nucleus and cytoplasm and that this alternative regulation of telomerase is key for functionally blocking its activity as an adjuvant target for chemotherapeutics for breast cancer.