Chromatin HMG-I (Y) as a Co-regulatory Protein for Estrogen Receptor Action in Breast Cancer Cells

摘要

Steroid hormones have rapid non-genomic effects on cell signaling pathways, but the receptor mechanisms responsible for this effect are not understood. We have identified a specific polyproline helix motif in the amino- terminal domain of conventional progesterone receptor (PR) that mediates direct progestin-dependent interaction of PR with SH3 domains of various cytoplasmic signaling molecules, including c-Src tyrosine kinases. Through this interaction, PR is a potent activator of Src kinases working by an SH3 domain displacement mechanism. By mutagenesis we also show that rapid progestin-induced activation of Src and down-stream NAP kinase in mammalian cells is dependent on PR-SH3 domain interaction, but not on the transcriptional activity of PR. Evidence for biological significance of this non-genomic PR signaling pathway through regulatory SH3 domains was shown with respect to an influence on progestin- induced growth arrest of breast epithelial cells and induction of Xenopus oocyte maturation.