Liganded and Unliganded Steroid Receptor Modulation of Beta 1 Adrenergic Receptor Gene Transcription

Abstract

The classical model of gene regulation by hormones involves a hormone-bound receptor interacting with a DNA response element to increase or decrease gene transcription. Steroid hormone regulation more commonly involves atypical cis-elements, co-receptors, accessory proteins, and unique modes of interaction on different genes. The thyroid hormone and retinoic acid receptors belong to the super family of steroid nuclear receptors and may modify gene expression even in the absence of ligand binding. In these studies, we characterized thyroid receptor-and retinoic acid receptor-mediated regulation of ␤1 adrenergic receptor (␤1AR) gene expression. Using cloned fragments of the ovine ␤1AR in a luciferase reporter vector, we examined the effects of thyroid receptor and retinoic acid receptor, alone and in combination with T3 or retinoic acid on ␤1AR expression. We examined expression in SK-N-SH neuroblastoma cells, CV-1 fibroblasts, and, in neonatal rat, primary cardiomyocytes. We demonstrated that even in the absence of ligand binding, thyroid receptor and retinoic acid receptor can significantly increase ␤1AR transcription activity. This effect is important in the developmental transition in ␤1AR expression during fetal and postnatal life. The classical model of gene regulation by hormones involves a hormone-bound receptor interacting with a DNA response element to increase or decrease gene transcription (1, 2). It is now appreciated that this model of hormonal regulation of gene expression is simplistic and may be the exception rather than the rule. For instance, classical models cannot explain the hormonal regulation of genes that lack canonical consensus DNA elements. These models also do not account for changes in hormonal regulation of gene expression at different developmental stages, differential regulation in different tissues, and other complexities of hormonal regulation. Steroid hormone regulation more commonly involves atypical cis-elements, co-receptors, accessory proteins, and unique modes of interaction on different genes (3).The TR and RAR belong to the super family of steroid nuclear receptors (1-4). TR and RAR bind to DNA as heterodimers with RXR (4). There is also a family of coregulators that positively and negatively regulate transcriptional activation from a variety of cis-elements in specific genes. Recently, it has been recognized that modulation of gene expression by steroid nuclear receptors may be independent of ligand binding to the steroid receptor. TR can bind to DNA in the absence of its ligand (thyroid hormone) and can regulate transcription both positively and negatively from a variety of promoters (5-7). Transactivation by TR in the absence of hormone can require cell-specific factors but may occur even with promoters that do not contain clearly defined TRE (8, 9). Similar observations have been reported for RAR (10). A precise physiologic context for nonligand-dependent regulation of transcription by these receptors has not been shown.We are interested in the hormonal regulation of ...

Alterations of L-Type Calcium Current and Cardiac Function in CaMKIIδ Knockout Mice

“…Major transcriptional regulators of β-AR genes include glucocorticoid- and thyroid hormone-responsive elements (GREs and TREs, respectively), with glucocorticoids downregulating β1-ARs and upregulating β2-ARs29. Thyroid hormone can upregulate β1-AR gene transcriptional activity30 whereas chronic exposure to β-AR-agonist results in downregulation of β1-AR protein and mRNA31. In the present study, we observed an increase in β2-AR/G i proteins in CaMKIIδ KO mice.…”