60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Gallo‐Payet, Nicole

doi:10.1530/jme-15-0257

Cited by 81 publications

(56 citation statements)

References 230 publications

(227 reference statements)

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“…Several effects of ACTH in adrenal cells are mediated by the activation of the cAMP/PKA pathway (Kimura 1986, Schimmer 1995, Gallo-Payet & Payet 2003, Sabban et al 2004, Gallo-Payet 2016. As stated previously, among them we have demonstrated the participation of the cAMP/PKA pathway in the transcriptional stimulation of HO-1 by ACTH (Pomeraniec et al 2004).…”

Section: Discussionsupporting

confidence: 79%

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Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Astort

Repetto

Rocha-Viegas

et al. 2016

Journal of Molecular Endocrinology

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In addition to the well-known function of ACTH as the main regulator of adrenal steroidogenesis, we have previously demonstrated its effect on the transcriptional stimulation of HO-1 expression, a component of the cellular antioxidant defense system. In agreement, we hereby demonstrate that, in adrenocortical Y1 cells, HO-1 induction correlates with a significant prevention of the generation of reactive oxygen species induced by H 2 O 2 /Fe 2+ . ACTH/cAMP-dependent activation of redox-imbalanced related factors such as NRF2 or NFκB and the participation of MAPKs in this mechanism was, however, discarded based on results with specific inhibitors and reporter plasmids. We suggest the involvement of CREB in HO-1 induction by ACTH/cAMP, as transfection of cells with a dominant-negative isoform of CREB (DN-CREB-M1) decreased, while overexpression of CREB increased HO-1 protein levels. Sequence screening of the murine HO-1 promoter revealed CRE-like sites located at −146 and −37 of the transcription start site and ChIP studies indicated that this region recruits phosphorylated CREB (pCREB) upon cAMP stimulation in Y1 cells. In agreement, H89 (PKA inhibitor) or cotransfection with DN-CREB-M1 prevented the 8Br-cAMP-dependent increase in luciferase activity in cells transfected with pHO-1[−295/+74].LUC. ACTH and cAMP treatment induced the activation of the PI3K/Akt signaling pathway in a PKA-independent mechanism. Inhibition of this pathway prevented the cAMP-dependent increase in HO-1 protein levels and luciferase activity in cells transfected with pHO-1[−295/+74].LUC. Finally, here we show a crosstalk between the cAMP/PKA and PI3K pathways that affects the binding of p-CREB to its cognate element in the murine promoter of the Hmox1 gene. CREB mediates adrenal HO-1 induction by cAMPf astort, e m repetto and others (Gallo-Payet 2016). In turn, stimulation of PKA activity is involved in the phosphorylation and activation of several transcription factors engaged in the transcriptional stimulation of steroidogenic-related genes. Among them, the cAMP response element binding protein (CREB), the GATA-4 binding protein, the steroidogenic factor 1 (SF1) and the CAAT enhancer binding protein (C/EBP) could be included (Manna et al. 2003a,b, Stocco et al. 2005.Glucocorticoid synthesis in the adrenal cortex is a multistep process where mitochondrial and microsomal cytochrome P450 enzymes, mixed function oxidases, catalyze the hydroxylation of steroids and the reduction of O 2 to water. Even under physiological conditions, ACTHstimulated steroidogenesis generates oxidative stress, as incomplete reduction in O 2 leads to the production of reactive oxygen species (ROS), lipoperoxides and other oxygenated species (Hanukoglu 2006, Prasad et al. 2014. To cope with the potentially damaging effects associated with oxidative stress, adrenal cells activate several antioxidant mechanisms (Chinn et al. 2002, Hanukoglu 2006, Battista et al. 2009). Among them, we have previously shown that the ACTH-dependent induction of heme oxygenase...

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Section: Discussionsupporting

confidence: 79%

“…Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway pathway (Gallo-Payet 2016). In turn, stimulation of PKA activity is involved in the phosphorylation and activation of several transcription factors engaged in the transcriptional stimulation of steroidogenic-related genes.…”

Section: Introductionmentioning

confidence: 99%

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Astort

Repetto

Rocha-Viegas

et al. 2016

Journal of Molecular Endocrinology

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“…Its exact mechanism is not entirely understood: it is suggested that increased concentrations of cortisol in the adrenal cortex directly inactivates the last steps of aldosterone synthesis in the ZG (27); there is also evidence that initial ZG cells undergo a differentiation process toward cortisol producing cells (28). …”

Section: Chronic Acth Excess In Man and Corticosteroid Secretionmentioning

confidence: 99%

“…The exact mechanism whereby ACTH promotes adrenocortical growth still is complex and remains partially understood, since in vitro studies show a paradoxical negative effect of ACTH on adrenocortical cell proliferation (36) The growth-stimulatory effect of ACTH in vivo most likely proceeds through the activation of a local and complex network of autocrine growth factors and their own receptors; a number substances, including non-ACTH POMC peptides such as γ3-MSH, have been shown to exert some adrenocortical growth effect (28). …”

Section: Chronic Acth Excess In Man and Adrenal Cortex Growthmentioning

confidence: 99%

Effects of Chronic ACTH Excess on Human Adrenal Cortex

Bertagna

2017

Front. Endocrinol.

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Chronic ACTH excess leads to chronic cortisol excess, without escape phenomenon, resulting in Cushing’s syndrome. Excess adrenal androgens also occur: in females, they will overcompensate the gonadotrophic loss, inducing high testosterone; in males, they will not compensate it, inducing low testosterone. Chronic ACTH excess leads to chronic adrenal mineralocorticoid excess and low aldosterone levels: after an acute rise, aldosterone plasma levels resume low values after a few days when ACTH is prolonged. Two other mineralocorticoids in man, cortisol and 11 deoxycorticosterone (DOC), at the zona fasciculata, will not escape the long-term effect of chronic ACTH excess and their secretion rates will remain elevated in parallel. Over all, the concomitant rise in cortisol and 11 DOC will more than compensate the loss of aldosterone, and eventually create a state of chronic mineralocorticoid excess, best evidenced by the accompanying suppression of the renin plasma levels, a further contribution to the suppression of aldosterone secretion. Prolonged in vivo stimulation with ACTH leads to an increase in total adrenal protein and RNA synthesis. Cell proliferation is indicated by an increase in total DNA the resulting adrenocortical hyperplasia participates in the amplified response of the chronically stimulated gland, and the weight of each gland can be greatly increased. The growth-stimulatory effect of ACTH in vivo most likely proceeds through the activation of a local and complex network of autocrine growth factors and their own receptors; a number of compounds, including non-ACTH proopiomelanocortin peptides such as γ3-MSH, have been shown to exert some adrenocortical growth effect.

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“…Aldosterone thus plays a central role in the regulation of blood pressure mainly by acting on the distal tubules and collecting ducts of the nephron. To a lesser extent, the adrenocorticotropic hormone (ACTH) also stimulates the secretion of aldosterone from adrenals (Gallo-Payet 2016). In healthy adults, the adrenal cortex produces 20-200 µg of aldosterone per day.…”

Section: :10mentioning

confidence: 99%

Genetics of primary hyperaldosteronism

Dutta

Söderkvist

Gimm

2016

Endocrine-Related Cancer

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Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.

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60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Cited by 81 publications

References 230 publications

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Effects of Chronic ACTH Excess on Human Adrenal Cortex

Genetics of primary hyperaldosteronism

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