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

摘要

The major goal of this research is to study the mechanism of corepressor proteins N-CoR in normal and breast cancer cells. It has been shown that N-CoR is capable of association with antagonist-bound estrogen receptor in the hormone-dependent human breast cancer (Shang et al., 2000). In addition, it has been shown that in the tamoxifen resistant breast cancer cells N-CoR expression level is decreased (Lavinsky et al, 1998). These observations highlight N-CoR as key regulators of breast cancer pharmacology. During the course of our research sponsored the current Postdoctoral Traineeship, we investigated N-CoR functions by identification of new N-CoR binding proteins and new mechanism that regulate N-CoR activities. The major findings are summarized as follows. First, we discovered that N-CoR physically interacts with B-Myb, a key cell cycle regulator. The significance of these B-Myb-corepressor interactions was confirmed by the finding that B-Myb mutants, which were unable to bind N-CoR, exhibited constitutive transcriptional activity. We also have determined that phosphorylation by cdk2/cyclin A blocks the interaction between B-Myb and N-CoR and that mutation of the corepressor binding site within B-Myb bypasses the requirement for this phosphorylation event. In our second finding, we discovered that corepressor N-CoR directly interacts with coactivator ACTR. Interestingly, ACTR is over-amplified in a number of breast cancer cells (Anzick et al., 1997). We observed that N-CoR contributes to transcriptional activation by recruiting ACTR to nuclear receptors prior to ligand activation. Our 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.