P/CAF Function in Transcriptional Activation by Steroid Hormone Receptors and Mammary Cell Proliferation

摘要

The purpose of this research is to investigate the role of histone acetyltransferases in the estrogen responses and the development and progression of breast tumors. Experiments were initially focused on one of these enzymes, PCAF. We have completed the major goals outlined in our original Statement of Work. Our studies have revealed that another acetylase, GCN5, is very highly related in both structure in and function to PCAF. However, loss of these two enzymes has dramatically different effects in mice. PCAF null mice are viable, fertile, and exhibit no defects in estrogen dependent processes. However loss of GCN5 leads to embryonic lethality due to loss of increased programmed cell death of mesodermal tissues. Moreover, GCN5 is genetically linked to BRCAl and provides a candidate for a tumor suppressor gene associated with spontaneous breast and ovarian cancers. Combined mutations in PCAF and GCN5 have even more severe effects on mouse development. These results suggest that both GCN5 and PCAF are important to embryogenesis. GCN5 is also important to the regulation of apoptosis and may play a role in tumor development.