Gene Regulation by Steroid Hormones

Abstract

Steroid hormones regulate the activity of certain genes by virtue of their specific interaction with the appropriate hormone receptors. Gene regulation is mediated by an interaction of the hormone receptors with specific DNA sequences located in the vicinity of the regulated promoter. The location and structure of the hormone regulatory elements (HRE) of different hormonally modulated genes is described. Binding studies and gene transfer experiments with a variety of constructs containing the HRE from the long terminal repeat (LTR) region of mouse mammary tumor virus (MMTV) demonstrate the molecular interaction and function of the glucocorticoid (GR) and progesterone (PR) receptors with this regulatory element. Both receptors interact with the same HRE of MMTV but there are differences in the binding and in the relevance of the individual sequence motifs for induction by each hormone. These experiments demonstrate that a functional cooperativity between the two binding regions of MMTV is necessary for the maximum hormonal response of the MMTV LTR. The protection pattern found in the MMTV promoter distal region using the hydroxyl radical footprinting technique is compatible with a model involving the interaction of a receptor dimer with the major grooves of four subsequent turns of the double helix. The binding of a functional steroid to either the glucocorticoid or progesterone receptor influences the kinetics of the protein-DNA interaction in vitro. The on-and off-rates are accelerated by binding of the hormone ligand, and this could facilitate scanning of the genomic DNA in search of HREs.