Reciprocal Regulation of a Glucocorticoid Receptor-Steroidogenic Factor-1 Transcription Complex on the Dax-1 Promoter by Glucocorticoids and Adrenocorticotropic Hormone in the Adrenal Cortex

Gummow, Brian M.; Scheys, Joshua O.; Cancelli, Victoria R.; Hammer, Gary D.

doi:10.1210/me.2005-0461

Cited by 101 publications

(87 citation statements)

References 56 publications

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“…Consistent with this, there is evidence that glucocorticoids can inhibit the transcription of steroidogenic genes through a mechanism that involves the synergistic association of SF-1 and GR to modulate DAX-1 expression (20). The present study provides further evidence to support this hypothesis by showing that a rapid, transient activation of adrenal GR tightly follows the dynamics of intra-adrenal corticosterone.…”

Section: Il-6supporting

confidence: 86%

“…1; see SI Appendix, Fig. S1 for the full SRN) (20)(21)(22)(23)(24)(25). Specifically, the model consists of a set of delay differential equations (DDEs) that describe the dynamics of intra-adrenal levels of CORT (A-CORT) and phosphorylation of GR (pGR, a marker of GR activation), and the expression of DAX-1, SF-1 and StAR following "virtual" (in silico) stimulation by ACTH (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For example, although DAX-1 expression is critical for normal HPA organ development (40)(41)(42), its role in regulating steroidogenesis in the adult is still unclear. SF-1 and GR have been shown to synergistically modulate DAX-1 expression (20), which in turn inhibits SF-1-mediated induction of StAR (43). ACTH is known to disrupt this SF-1/GR synergistic effect on DAX-1 (20), and GR is activated by intraadrenal CORT.…”

Section: Il-6mentioning

confidence: 99%

“…SF-1 and GR have been shown to synergistically modulate DAX-1 expression (20), which in turn inhibits SF-1-mediated induction of StAR (43). ACTH is known to disrupt this SF-1/GR synergistic effect on DAX-1 (20), and GR is activated by intraadrenal CORT. This suggests that DAX-1 may be acting as an organizing "hub" by simultaneously integrating and decoding hormone signals from both the pituitary and the adrenal to control steroidogenesis.…”

Section: Il-6mentioning

confidence: 99%

“…The biological processes underlying this self-inhibition are not known, but the glucocorticoid receptor (GR) is expressed in the adrenal cortex (15,18). Furthermore, the synthetic glucocorticoid dexamethasone-a specific GR agonist-has been shown to inhibit ACTH-induced corticosterone secretion from rat adrenocortical cells (19) as well as the transcription of steroidogenic genes through a mechanism that involves GRand SF-1-mediated induction of DAX-1 expression (20).…”

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confidence: 99%

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Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The hypothalamic-pituitary-adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress. T he hypothalamic-pituitary-adrenal (HPA) axis is a stressresponsive neuroendocrine system that controls circulating levels of the vital glucocorticoid (CORT) hormones corticosterone (in rodents) and cortisol (in humans). These are steroids synthesized by the adrenal gland in response to stimulation by adrenocorticotropic hormone (ACTH), which is secreted by the anterior pituitary in response to corticotrophin-releasing hormone (CRH) and arginine vasopressin released from hypothalamic paraventricular neurons. These neurons receive circadian inputs from the suprachiasmatic nucleus and are activated in response to stress. Via the bloodstream, CORT accesses target tissues where it mediates metabolic, cognitive, and immune responses. CORT also regulates its own production through negative feedback inhibition of ACTH and CRH secretion from the pituitary and hypothalamus, respectively. To mount an effective response to stress, CORT must be secreted rapidly by the adrenal glands. However, because of its lipophilic nature, CORT cannot be prestored in vesicles and must therefore be rapidly synthesized de novo in response to ACTH stimulation.Under basal, unstressed conditions, ACTH and CORT exhibit ultradian oscillations. Although there is some evidence for pulsatility of CRH (1, 2), our recent work suggests that ACTH and CORT pulsatility is predominantly generated by a subhypothalamic oscillator within the pituitary-adrenal system (3, 4). The amplitude of these pulses varies in a circadian manner with larger pulses occurring at the start of the active phase (morning in humans, evening in rodents). Under normal physiological conditions, CORT secretion is tightly correlated with ACTH (5). However, there are a number of conditions where a dynamic dissociation between these hormones occurs (reviewed in ref. 6). For example, there is evidence that proinflammatory cytokines released during inflammation can poten...

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Section: Il-6supporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Il-6mentioning

confidence: 99%

Section: Il-6mentioning

confidence: 99%

mentioning

confidence: 99%

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Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fetal Endocrinology

Katugampola¹,

Gevers²,

Dattani³

2019

Brook's Clinical Pediatric Endocrinology

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Adrenocortical Growth and Cancer

Lefèvre

Bertherat

Ragazzon

2014

Comprehensive Physiology

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The adrenal gland consists of two distinct parts, the cortex and the medulla. Molecular mechanisms controlling differentiation and growth of the adrenal gland have been studied in detail using mouse models. Knowledge also came from investigations of genetic disorders altering adrenal development and/or function. During embryonic development, the adrenal cortex acquires a structural and functional zonation in which the adrenal cortex is divided into three different steroidogenic zones. Significant progress has been made in understanding adrenal zonation. Recent lineage tracing experiments have accumulated evidence for a centripetal differentiation of adrenocortical cells from the subcapsular area to the inner part of the adrenal cortex. Understanding of the mechanism of adrenocortical cancer (ACC) development was stimulated by knowledge of adrenal gland development. ACC is a rare cancer with a very poor overall prognosis. Abnormal activation of the Wnt/β-catenin as well as the IGF2 signaling plays an important role in ACC development. Studies examining rare genetic syndromes responsible for familial ACT have played an important role in identifying genetic alterations in these tumors (like TP53 or CTNNB1 mutations as well as IGF2 overexpression). Recently, genomic analyses of ACT have shown gene expression profiles associated with malignancy as well as chromosomal and methylation alterations in ACT and exome sequencing allowed to describe the mutational landscape of these tumors. This progress leads to a new classification of these tumors, opening new perspectives for the diagnosis and prognostication of ACT. This review summarizes current knowledge of adrenocortical development, growth, and tumorigenesis.

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Reciprocal Regulation of a Glucocorticoid Receptor-Steroidogenic Factor-1 Transcription Complex on the Dax-1 Promoter by Glucocorticoids and Adrenocorticotropic Hormone in the Adrenal Cortex

Cited by 101 publications

References 56 publications

Dynamic responses of the adrenal steroidogenic regulatory network

Dynamic responses of the adrenal steroidogenic regulatory network

Fetal Endocrinology

Adrenocortical Growth and Cancer

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