Homologous steroid receptors assemble at identical promoter architectures with unique energetics of cooperativity.

Steroid receptors comprise a homologous family of ligand-activated transcription factors. The receptors bind largely identical response elements in vitro, yet regulate distinct gene networks in vivo. This paradox raises the issue of how transcriptional specificity is achieved, particularly if multiple receptor populations are competing for identical sites.

Steroid receptor-DNA interactions: toward a quantitative connection between energetics and transcriptional regulation.

Steroid receptors comprise an evolutionarily conserved family of transcription factors. Although the qualitative aspects by which individual receptors regulate transcription are well understood, a quantitative perspective is less clear. This is primarily because receptor function is considerably more complex than that of classical regulatory factors such as phage or bacterial repressors.

Dissection of androgen receptor-promoter interactions: steroid receptors partition their interaction energetics in parallel with their phylogenetic divergence.

Steroid receptors comprise a homologous family of ligand-activated transcription factors. The members include androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and progesterone receptor (PR). Phylogenetic studies demonstrate that AR, GR, MR, and PR are most closely related, falling into subgroup 3C.

Analysis of a glucocorticoid-estrogen receptor chimera reveals that dimerization energetics are under ionic control.

Steroid receptors assemble at DNA response elements as dimers, resulting in coactivator recruitment and transcriptional activation. Our work has focused on dissecting the energetics associated with these events and quantitatively correlating the results with function. A recent finding is that different receptors dimerize with large differences in energetics.

Glucocorticoid receptor-DNA interactions: binding energetics are the primary determinant of sequence-specific transcriptional activity.

The glucocorticoid receptor (GR) is a member of the steroid receptor family of ligand-activated transcription factors. A long-standing question has focused on how GR and other receptors precisely control gene expression. One difficulty in addressing this is that GR function is influenced by multiple factors including ligand and coactivator levels, chromatin state, and allosteric coupling.

Glucocorticoid receptor-promoter interactions: energetic dissection suggests a framework for the specificity of steroid receptor-mediated gene regulation.

The glucocorticoid receptor (GR) is a member of the steroid receptor family of ligand-activated transcription factors. A number of studies have shown that steroid receptors regulate distinct but overlapping sets of genes; however, the molecular basis for such specificity remains unclear. Previous work from our laboratory has demonstrated that under identical solution conditions, three other steroid receptors [the progesterone receptor A isoform (PR-A), the progesterone receptor B isoform (PR-B), and estrogen receptor α (ER-α)] differentially partition their self-association and promoter binding energetics.

Thermodynamic dissection of estrogen receptor-promoter interactions reveals that steroid receptors differentially partition their self-association and promoter binding energetics.

Steroid receptors define a family of ligand-activated transcription factors. Recent work has demonstrated that the receptors regulate distinct but overlapping gene networks, yet the mechanisms by which they do so remain unclear. We previously determined the microscopic binding energetics for progesterone receptor (PR) isoform assembly at promoters containing multiple response elements.

Na(+) and K(+) allosterically regulate cooperative DNA binding by the human progesterone receptor.

Cooperativity is a common mechanism used by transcription factors to generate highly responsive yet stable gene regulation. For the two isoforms of human progesterone receptor (PR-A and PR-B), differences in cooperative DNA binding energetics may account for their differing transcriptional activation properties. Here we report on the molecular origins responsible for cooperativity, finding that it can be activated or repressed with Na(+) and K(+), respectively.

Thermodynamic dissection of progesterone receptor interactions at the mouse mammary tumor virus promoter: monomer binding and strong cooperativity dominate the assembly reaction.

Progesterone receptors (PRs) play critical roles in eukaryotic gene regulation, yet the mechanisms by which they assemble at their promoters are poorly understood. One of the few promoters amenable to analysis is the mouse mammary tumor virus gene regulatory sequence. Embedded within this sequence are four progesterone response elements (PREs) corresponding to a palindromic PRE and three half-site PREs.

Coactivator assembly at the promoter: efficient recruitment of SRC2 is coupled to cooperative DNA binding by the progesterone receptor.

A largely unsolved problem in eukaryotic gene regulation focuses on the mechanisms by which DNA-bound transcription factors recruit coactivators to a promoter. Recent work has suggested that promoter DNA acts as an allosteric ligand, serving not only to bind and localize transcription factors but also to trigger structural changes within the proteins in order to elicit coactivator recruitment. Unfortunately, a quantitative and molecular understanding of this phenomenon remains unclear.

Thermodynamic analysis of progesterone receptor-promoter interactions reveals a molecular model for isoform-specific function.

Human progesterone receptors (PR) exist as two functionally distinct isoforms, PR-A and PR-B. The proteins are identical except for an additional 164 residues located at the N terminus of PR-B. To determine the mechanisms responsible for isoform-specific functional differences, we present here a thermodynamic dissection of PR-A-promoter interactions and compare the results to our previous work on PR-B.

Nuclear receptor structure: implications for function.

Small lipophilic molecules such as steroidal hormones, retinoids, and free fatty acids control many of the reproductive, developmental, and metabolic processes in eukaryotes. The mediators of these effects are nuclear receptor proteins, ligand-activated transcription factors capable of regulating the expression of complex gene networks. This review addresses the structure and structural properties of nuclear receptors, focusing on the well-studied ligand-binding and DNA-binding domains as well as our still-emerging understanding of the largely unstructured N-terminal regions.

Hydrodynamic analysis of the human progesterone receptor A-isoform reveals that self-association occurs in the micromolar range.

Human progesterone receptors exist as two functionally distinct isoforms, an 83 kDa A-receptor (PR-A) and a 99 kDa B-receptor (PR-B). The isoforms are identical except that PR-B has an additional 164 amino acids at its N-terminus. We have previously characterized the hydrodynamics and solution assembly energetics of PR-B [Heneghan, A.

Cooperative DNA binding by the B-isoform of human progesterone receptor: thermodynamic analysis reveals strongly favorable and unfavorable contributions to assembly.

Progesterone receptors (PR) play critical roles in eukaryotic gene regulation, yet the mechanisms by which they assemble at multisite promoters are poorly understood. Here we present a thermodynamic analysis of the interactions of the PR B-isoform (PR-B) with promoters containing either one or two progesterone response elements (PREs). Utilizing quantitative footprinting, we have resolved the microscopic energetics of PR-B binding, including cooperativity terms.

Self-association energetics of an intact, full-length nuclear receptor: the B-isoform of human progesterone receptor dimerizes in the micromolar range.

We are focused on understanding the mechanisms underlying eukaryotic gene regulation, using the human progesterone receptor (PR) and its interactions with its DNA response elements as a model system. An understanding of PR function is complicated by the presence of two transcriptionally distinct isoforms, an 83 kDa A-receptor (PR-A) and a 99 kDa B-receptor (PR-B). The two isoforms are identical except the B-receptor contains an additional 164 residues at its N-terminus.