Differential Regulation of Cell Cycle Progression in Human Breast Cancer

Factors that mediate chemical or structural alterations of chromatin have been implicated as mediators of nuclear receptor function. Prominent in this diverse group of putative coactivators is the Steroid Receptor Coactivator-1 (SRC-1) and its related factors. These factors physically interact with liganded nuclear receptors and couple them to the multifunctional coactivators such as p3OO and CPB which have both intrinsic and associated histone acetyltransferase (HAT) activity. Other studies have suggested that factors involved in the structural remodeling of chromatin are required for nuclear receptor function. One such factor, the Brahma Related Gene-i (BRG- 1) potentiates nuclear receptor signaling and has been shown to be associated with liganded nuclear receptors. Like p3OO and CBP, we find that BRG-I exists in a stable complex with SRC- 1, and this complex can be recruited to a hormone bound estrogen receptor (ER). We demonstrate that in vitro the hormone-dependent association between BRG-1 and ER is mediated by SRC-1, and that structural determinants of ER required for SRC- I binding overlap with those required for the association between ER and BRG- 1. Furthermore, we present data that coactivation of ER signaling by either SRC- 1 or CBP requires BRG- 1. In addition we show that the BRG- 1-mediated coactivation of ER signaling is synergistically enhanced by inhibition of histone deactylation. These studies suggest that SRC- 1 functions as an adaptor that links two distinct classes of coactivators to nuclear receptor signaling.