Corepressor Associated Peptides (CAPS): Tools to Elucidate the Role of Corepressors as Regulators of Progesterone Receptor Transcriptional Activity

摘要

Progesterone regulates diverse aspects of proliferation, differentiation and development of mammary, uterine and nervous tissues. The biological functions of progesterone are mediated through the progesterone receptor (PR) whose transcriptional activities are modulated by corepressors and coactivators. We are interested in studying the interaction between corepressors and PR with a view of evaluating the role of this complex on the pharmacology of progestins and anti-progestins in breast cancer. Our group observed that corepressor N-CoR binds to antagonist-bound PR in cells and suppresses 8-bromo- cAMP mediated potentiation of PR transcriptional activity (Wagner et at., 1998). Over-expression of N-CoR represses the partial agonist activity of RU486-bound PR (Jackson et at., 1997). These observations highlight N- CoR as key regulators of PR pharmacology. In the first year of this research we undertook a phage display approach to identify the protein-protein interaction surfaces on N-CoR. Among the phage peptides associating with N-CoR, one peptide shared striking similarity to coactivator ACTR. This finding has subsequently lead to the discovery that corepressor N-CoR directly interacts with coactivator ACTR. Our research results suggested that transcriptional repression and activation, the two processes which both involved in breast cancer biology, are integrated in a manner that are not previously anticipated. We will next test how corepressors and coactivators coordinate in regulating progesterone action in normal and breast cancer cells.