Differential hormone-dependent transcriptional activation and -repression by naturally occurring human glucocorticoid receptor variants

The molecular mechanisms underlying primary glucocorticoid resistance or hypersensitivity are not well understood. Using transfected COS-1 cells as a model system, we studied gene regulation by naturally occurring mutants of the glucocorticoid receptor (GR) with single-point mutations in the regions encoding the ligand-binding domain or the N-terminal domain reflecting different phenotypic expression. We analyzed the capacity of these GR variants to regulate transcription from different promoters, either by binding directly to positive or negative glucocorticoid-response elements on the DNA or by interfering with protein-protein interactions. Decreased dexamethasone (DEX) binding to GR variants carrying mutations in the ligand-binding domain correlated well with decreased capacity to activate transcription from the mouse mammary tumor virus (MMTV) promoter. One variant, D641V, which suboptimally activated MMTV promoter-mediated transcription, repressed a PRL promoter element containing a negative glucocorticoid-response element with wild type activity. DEX-induced repression of transcription from elements of the intercellular adhesion molecule-1 promoter via nuclear factor-kappaB by the D641V variant was even more efficient compared with the wild type GR. We observed a general DEX-responsive AP-1-mediated transcriptional repression of the collagenase-1 promoter, even when receptor variants did not activate transcription from the MMTV promoter. Our findings indicate that different point mutations in the GR can affect separate pathways of gene regulation in a differential fashion, which can explain the various phenotypes observed

Stress and sex versus immunity and inflammation

Glucocorticoids, the major effector hormones of the stress system, influence almost all aspects of mammalian physiology. These steroids exert their effects on a large network of primary, secondary, and tertiary target genes, encompassing up to 20% of the expressed genome in a tissue. New evidence shows quantitative and qualitative gender-specific differences in the actions of glucocorticoids on the rat liver transcriptome, suggesting that the pervasive actions of these hormones are modulated by gender, both as an inherent property of the target tissues and as a result of exposure of these tissues to estrogens and possibly also androgens. Generally, albeit not always, female mammals have more robust behavioral and somatic responses to stress and more potent immune and inflammatory reactions than males - differences that are inherent, sex steroid - mediated, or both and possibly the evolutionary products of natural selection of female and male roles

Organization and Integration of the Endocrine System: The Arousal and Sleep Perspective

This article focuses on the neuroendocrine infrastructure of the adaptive response to stress and on its effects on the major endocrine axes in the body. Also discussed is the altered regulation or dysregulation of the adaptive response in various physiologic and pathophysiologic states, which may influence the growth and development of an individual and define the vulnerability of this individual to endocrine, psychiatric, or immunologic disease

Stress and disorders of the stress system

All organisms must maintain a complex dynamic equilibrium, or homeostasis, which is constantly challenged by internal or external adverse forces termed stressors. Stress occurs when homeostasis is threatened or perceived to be so; homeostasis is re-established by various physiological and behavioral adaptive responses. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats, and are involved in the pathogenesis of diseases characterized by dyshomeostasis or cacostasis. The stress response is mediated by the stress system, partly located in the central nervous system and partly in peripheral organs. The central, greatly interconnected effectors of this system include the hypothalamic hormones arginine vasopressin, corticotropin-releasing hormone and pro-opiomelanocortin-derived peptides, and the locus ceruleus and autonomic norepinephrine centers in the brainstem. Targets of these effectors include the executive and/or cognitive, reward and fear systems, the wake-sleep centers of the brain, the growth, reproductive and thyroid hormone axes, and the gastrointestinal, cardiorespiratory, metabolic, and immune systems. Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being, successful performance of tasks, and appropriate social interactions. By contrast, excessive or inadequate basal activity and responsiveness of this system might impair development, growth and body composition, and lead to a host of behavioral and somatic pathological conditions. © 2009 Macmillan Publishers Limited. All rights reserved

Glucocorticoid resistance syndromes and states

www.ENDOTEXT.OR

Milestones in CRH research

The Corticotropin-releasing Hormone (CRH) mammalian family members include CRH, urocortin I, Stresscopin (SCP) and Stresscopin-related peptide (SRP), along with the CRH receptors type 1 (CRHR1) and type 2 (CRHR2), and CRH-binding protein (CRH-BP). These family members differ in their tissue distribution and pharmacology. Several studies have provided evidence supporting an important role of this family in the regulation of the neuroendocrine and behavioral responses to stress. Regulation of the relative contribution of CRH and its homologs and the two CRH receptors in brain CRH pathways may be essential in coordinating physiologic responses to stress. The development of disorders related to heightened stress sensitivity and dysregulation of stress-coping mechanisms appears to involve regulatory mechanisms of the CRH family members. Therapeutic agents that target CRH family members may offer a new approach to the treatment of these disorders. The purpose of this review is to summarize the most significant discoveries related to CRH over time. © 2017 Bentham Science Publishers

Bilateral adrenal incidentalomas and NR3C1 mutations causing glucocorticoid resistance: Is there an association?

Glucocorticoids signal through their cognate, ubiquitously expressed glucocorticoid receptor (GR), which influences the transcription of a large number of target genes. Several genetic defects, including point mutations, deletions or insertions in the NR3C1 gene that encodes the GR, have been associated with familial or sporadic generalized glucocorticoid resistance or Chrousos syndrome. One of the clinical manifestations of this rare endocrine condition is bilateral adrenal hyperplasia due to compensatory elevations of plasma ACTH concentrations. In this commentary, we discuss the interesting findings of the recently published French MUTA-GR study and present our perspective on the evolving field of NR3C1 pathology. © 2018 European Society of Endocrinology