Differential Regulation of Cell Cycle Progression in Human Breast Cancer Cell Lines by the Estrogen Receptor

摘要

The goal of DOD grant DAMD17-97-1-7069 is to understand the mechanisms by which ER mediates gene regulation and cell cycle progression. Estrogen-bound ER undergoes structural changes which favor the recruitment of factors that modify the chemical and structural composition of chromatin. These factors bind activated receptors thereby coupling them to multifunctional histone acetyltransferases such as CBP/p300 and PCAF. Additionally, chromatin remodeling factors also mediate hormone-dependent transcriptional activation by nuclear receptors. Among these, the Brahma Related Gene-1 (BRG-1) potentiates the transcriptional activation. These studies indicate that distinct mechanisms, that target the chemical and structural composition of chromatin contribute to nuclear receptor activity. Our results demonstrate that BRG-1 is recruited to ER in a hormone and AF-2-dependent manner and is essential for ER-mediated transcriptional activation. In the absence of BRG- 1 neither SRC-1 nor CBP is capable of coactivating ER signaling. Finally we demonstrate that ERG-1 mediated coactivation of ER is increased by inhibition of histone deacetylation and decreased by overexpression of Histone Deacetylase-1 (HDAC-1). These studies support a model for ER action in which either histone acetylation or chromatin remodeling are sufficient to potentiate a transcriptional response alone but that together these systems function cooperatively to produce an enhanced hormonal response.