Targeting the Estrogen Receptor for Ubiquitination and Degradation in Breast Cancer Cells
Abstract
The ubiquitin-proteasome pathway involves the assembly of a multiubiquitin chain on a substrate, which then targets the appended protein for degradation by the 26S proteasome. In this application, we propose to develop a suite of heterobifunctional compounds known as Protacs (for Proteolysis -Targeting Chimeric Molecules) that can be used to target the degradation of any protein in the cell by artificially tethering it to a ubiquitin ligase. Specifically, we propose to investigate a Protac that is comprised of a peptide epitope derived from IkappaBalpha (IkBa) linked to estradiol (E2). The IkBa peptide binds specifically to the ubiquitin ligase SCF(exp beta-TRCP) whereas estradiol binds specifically to ER, The underlying hypothesis of the work proposed here is that Protac (and subsequent Protacs) will serve as a molecular bridge that links ER toSCF(exp beta-TRCP). This linkage, in turn, will promote ubiquitination and degradation of ER, which is expected to inhibit the growth of hormone-responsive breast cancer cells. The specific aims are: (1) that a cell permeable Protac will enter breast cancer cells; (2) that Protac will activate turnover of ER in breast cancer cells; and (3) that Protacs will have an effect on the growth of breast cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2004
- Accession Number
- ADA432056
Entities
People
- Kathleen M. Sakamoto
Organizations
- University of California, Los Angeles