Steroid Receptor Family: Structure and Functions

Abstract

Steroid receptors are a class of molecules that function as both signal transducers and transcription factors. From cloned sequences it is apparent that steroid receptors and other transcription factors belong to a superfamily of proteins that appear to function by similar mechanisms. Functional domains for hormone and DNA binding, and for transcriptional activation, have been defined for several receptors. In some cases, specific amino acids required for function have been identified. The multi-functional steroid receptor molecules are modular in nature in that domains function independently of structural position in receptor molecules and can even function after insertion into unrelated transactivation proteins. The mechanism of receptor action is complex and multistage and a number of unanswered questions remain to be defined. Receptors are inactive in the absence of hormone in vivo; the proposed components of this inactive complex include several proteins and RNA. Theories on the physiological role of HSP 90 in this complex range from an artifactual interaction to an absolute conformational requirement for hormone binding. Although its function has not been demonstrated clearly yet, there is a consensus that one major function is to inactivate receptor by blocking DNA binding. Most of the steroid receptors appear to be nuclear in the absence of hormone. The transformation process produces a receptor molecule that is capable of specific DNA binding and transcriptional activation. The specificity of DNA binding is conferred by as few as three amino acids in the first finger of the C1 region. Receptors appear to bind to DNA as dimers although whether dimers are preformed in cytoplasm remains unknown. Although the DNA binding domain is required for gene activation, other regions of the molecule in the carboxyl and amino terminus enhance activation function. Important interactions of steroid receptors with other receptors and unrelated transcription factors has been proposed and most certainly occurs. Finally, posttranslational modifications such as phosphorylation have been postulated to modulate several functional properties of steroid receptors.

DNA Recognition by Normal and Oncogenic Thyroid Hormone Receptors

“…We also disfavor a model in which the N terminus mediates its effects indirectly by altering the conformation of the target DNA; although both v-ErbA and c-ErbA induce DNA bending, the extent of the bend is independent of the nature of the N terminus. 2 Instead, we suggest that the receptor N terminus acts indirectly by influencing the tertiary conformation of the zinc-finger P-and A-box helices. We propose that although the P-and A-box amino acids make the actual discriminatory contacts with bases in the DNA, the N terminus can alter the precise position or orientation of the zinc-finger recognition helices and thus can define in a global fashion the exact base contacts made, and the stringency of the protein-DNA interaction.…”

“…The nuclear hormone receptors are a family of ligand-regulated transcription factors that mediate cellular responses to a broad range of small hydrophobic hormones (1)(2)(3)(4)(5). Members of the family include the steroid receptors, the retinoid acid receptors (RARs), 1 retinoid X receptors (RXRs), and the thyroid hormone receptors (T 3 Rs).…”

Changing colors in mice: an inducible system that delivers: Figure 1.

“…Both the estrogen-and progesterone-based inducible systems use nuclear hormone receptors that are able to respond to ligand binding by dissociating from their inactivating complexes, forming dimers, binding DNA, and activating transcription (Evans 1988;Carson-Jurica et al 1990;Pratt and Toft 1997). The progesterone-based system uses a chimeric regulator, GLVP.…”

Human vascular smooth muscle cells express an estrogen receptor isoform

“…However, the signaling pathways involved in the direct effects of E2 on vascular cells are not yet characterized. In non-vascular cells, most E2-mediated effects are thought to result from ligand-induced activation of the intracellular E2 receptor, a transcription factor capable of regulating expression of genes whose regulatory elements contain a consensus E2 receptor binding sequence (reviewed in [31][32][33][34]). Human vascular smooth muscle cells are now known to express an E2 receptor [1,35].…”