NUCLEAR HORMONE RECEPTORS: REGULATORS OF GENE EXPRESSION

Abstract

Over the past three decades, a great deal of evidence has accumulated in favor of the hypothesis that steroid hormones act via regulation of gene expression. The action is mediated by specific nuclear receptor proteins, which belong to a superfamily of ligand-modulated transcription factors that regulate homeostasis, reproduction, development and differentiation. This family includes receptors for steroid hormones, thyroid hormones and hormonal forms of vitamin A and D. All members of this superfamily have a similar functional domain structure: a variable N-terminal region, which is involved in modulation of gene expression. A short well conserved DNA-binding domain, which is crucial for recognition of specific DNA sequences and for receptor dimerization; and a partially conserved C-terminal hormone-binding domain. Hormone-receptor complexes regulate gene expression by binding to hormone-response elements which are located in the 5′-flanking sequences of hormone-responsive genes. Binding of nuclear hormone receptors to their cognate hormone response elements occurs as dimers. Receptors enhance transcription by stabilizing general transcription factors either directly at the TATA-box or through interactions with proteins bound to upstream promoter sequences or via interaction with transcription intermediairy factors which can be considered as coupling proteins between the receptor and other protein components in the transcription initiation complex. Receptor gene defects are frequently the cause of several forms of hormone resistance.