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

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 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

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

Sex differences in circadian endocrine rhythms: Clinical implications

Organisms have developed a highly conserved and tightly regulated circadian system, to adjust their daily activities to day/night cycles. This system consists of a central clock, which is located in the hypothalamic suprachiasmatic nucleus, and the peripheral clocks that are ubiquitously expressed in all tissues. Both the central and peripheral clocks communicate with each other and achieve circadian oscillations of gene expression through transcriptional/translational loops mediated by clock transcription factors. It is worth mentioning that circadian non-transcriptional/non-translational rhythms also occur in non-nucleated cells. Interestingly, sex has been identified as an important factor influencing the activity of the circadian system. Indeed, several sex differences have been documented in the anatomy, physiology and pathophysiology that pertain to circadian rhythms. In this review, we present the historical milestones of understanding circadian rhythms, describe the central and peripheral components of the circadian clock system, discuss representative examples of sexual dimorphism of circadian rhythms, and present the most relevant clinical implications. © 2020 Federation of European Neuroscience Societies and John Wiley & Sons Lt

Glucocorticoid resistance syndromes and states

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Glucocorticoid resistance syndromes and states

www.ENDOTEXT.OR