The expression of inhibin/activin subunits in the human adrenal cortex and its tumours

Munro, L. M. A.; Kennedy, Alex. Mills; McNicol, Anne Marie

doi:10.1677/joe.0.1610341

Cited by 86 publications

(66 citation statements)

References 29 publications

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“…Inhibins antagonize activin signaling through binding the activin type II receptor and formation of an inactive complex with the TGFb type III receptor b-glycan. In the normal human adrenal cortex, expression of inhibin a-subunit is mainly observed in zona reticularis while b-subunit is principally expressed in the outer zones (211,212). In agreement with this observation, expression of inhibin a-subunit is predominantly stimulated by ACTH whereas that of inhibin b-subunit is activated by ANG II (45).…”

Section: Factorssupporting

confidence: 75%

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Lefebvre

Prévost

Louiset

2013

European Journal of Endocrinology

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A wide variety of autocrine/paracrine bioactive signals are able to modulate corticosteroid secretion in the human adrenal gland. These regulatory factors, released in the vicinity of adrenocortical cells by diverse cell types comprising chromaffin cells, nerve terminals, cells of the immune system, endothelial cells, and adipocytes, include neuropeptides, biogenic amines, and cytokines. A growing body of evidence now suggests that paracrine mechanisms may also play an important role in the physiopathology of adrenocortical hyperplasias and tumors responsible for primary adrenal steroid excess. These intra-adrenal regulatory systems, although globally involving the same actors as those observed in the normal gland, display alterations at different levels, which reinforce the capacity of paracrine factors to stimulate the activity of adrenocortical cells. The main modifications in the adrenal local control systems reported by now include hyperplasia of cells producing the paracrine factors and abnormal expression of the latter and their receptors. Because steroid-secreting adrenal neoplasms are independent of the classical endocrine regulatory factors angiotensin II and ACTH, which are respectively suppressed by hyperaldosteronism and hypercortisolism, these lesions have long been considered as autonomous tissues. However, the presence of stimulatory substances within the neoplastic tissues suggests that steroid hypersecretion is driven by autocrine/paracrine loops that should be regarded as promising targets for pharmacological treatments of primary adrenal disorders. This new potential therapeutic approach may constitute an alternative to surgical removal of the lesions that is classically recommended in order to cure steroid excess.European Journal of Endocrinology 169 R115-R138

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Section: Factorssupporting

confidence: 75%

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Lefebvre

Prévost

Louiset

2013

European Journal of Endocrinology

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“…By secreting inhibins, the AC cell line resembles the adrenal cortex and tumours arising from it, which strongly express the inhibin -subunit and weakly express both -subunits (Crawford et al 1987, Voutilainen et al 1991, Munro et al 1999, Arola et al 2000, and the human AC H295R cell line, which also makes and secretes activin A and both inhibin A and inhibin B (Vanttinen et al 2002). The present results also show that AC cells express mRNA encoding several BMP/GDF ligands (BMP-2, -3, -4, -6 and -8a; GDF-1, -3, -5 and -9) and Lefty A and B, for which autocrine roles in the adrenal cortex are yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

Rodent adrenocortical cells display high affinity binding sites and proteins for inhibin A, and express components required for autocrine signalling by activins and bone morphogenetic proteins

Farnworth¹,

Wang²,

Leembruggen³

et al. 2006

Journal of Endocrinology

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Inhibins are expressed in the adrenal cortex, but little is known of their binding or role in the adrenal. The aims of the present study were, first, to establish whether a mouse adrenocortical (AC) cell line expresses inhibins/activins and bone morphogenetic proteins (BMP), along with proteins required for inhibin to antagonise activin and BMP actions and, secondly, to characterise and compare inhibin binding sites and proteins in the rat adrenal gland and AC cells. AC cells were found to: (1) express mRNA for multiple BMPs (BMP-2, -3, -4, -6, -8a), growth/ differentiation factors (GDF-1, -3, -5, -9), Lefty A and B, and the inhibin , A and B subunits (2) secrete inhibin A and inhibin B and (3) express mRNA encoding the inhibin co-receptor, betaglycan, along with activin and BMP type I (ALK2-7) and type II (ActRII, ActRIIB, BMPRII) receptors, and binding proteins (follistatin, BAMBI, gremlin ]inhibin A on both the primary rat adrenal and AC cells. The species of >220 kDa were shown by immunoprecipitation to include betaglycan, the species of 105 kDa is consistent in size with type II receptors for activin/BMP, and that of 62 kDa co-migrates with the inhibin-follistatin complex.In summary, the results show that inhibin A binds selectively and with both high and low affinity to AC cells via multiple binding proteins, including a single betaglycan-like species. The results support the role of glycosylated betaglycan in the high affinity binding of inhibin A, but provide consistent evidence from two independent sources of adrenal cells that inhibin A interacts with several membrane proteins in addition to those currently understood to mediate the anti-activin/BMP actions of inhibin.

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“…Very recently, Munro et al (1999) suggested that loss of inhibin immunopositivity in some adrenocortical carcinomas is an indicator of tumour progression. We did not find that inhibin expression reflects the malignant potential of the tumour, as 29% of the adenomas and 23% of the carcinomas were negative for inhibin .…”

Section: Discussionmentioning

confidence: 99%

Expression of inhibin alpha in adrenocortical tumours reflects the hormonal status of the neoplasm

Arola

Liu²,

Heikkilä³

et al. 2000

Journal of Endocrinology

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Inhibins are gonadal glycoprotein hormones whose main endocrine function is to inhibit pituitary FSH secretion. In addition to testes and ovaries, other steroid-producing organs are sites of inhibin subunit expression. To study the role of inhibins in human adrenal gland, we screened a panel of 150 adrenals (10 normal adrenals, 25 adrenocortical hyperplasias, 65 adrenocortical adenomas, 30 adrenocortical carcinomas and 20 phaeochromocytomas) for inhibin expression. mRNA levels of inhibin subunit were studied in 57 samples and all tissues were stained immunohistochemically with an inhibin subunit-specific antibody. Inhibin mRNA was detected in all adrenocortical tissues. Virilizing adenomas possessed a 10-fold higher median inhibin mRNA expression than did normal adrenals. Bilaterally and nodularly hyperplastic adrenals and other than virilizing adrenocortical tumours had their median inhibin mRNA levels close to those of normal adrenals. Immunohistochemically, inhibin subunit was detectable in all normal and hyperplastic adrenals, as well as in 73% of the adrenocortical tumours. However Our data show that inhibin subunit is highly expressed in both normal and neoplastic androgenproducing adrenocortical cells, with less expression in cortisol-producing and hardly any in aldosteroneproducing cells. This suggests a specific role for inhibins in the regulation of adrenal androgen production. We did not find any significant difference in inhibin expression between benign and malignant adrenocortical tumours. Thus inhibin gene does not seem to have a tumour suppressor role in human adrenal cortex.

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The expression of inhibin/activin subunits in the human adrenal cortex and its tumours

Cited by 86 publications

References 29 publications

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Rodent adrenocortical cells display high affinity binding sites and proteins for inhibin A, and express components required for autocrine signalling by activins and bone morphogenetic proteins

Expression of inhibin alpha in adrenocortical tumours reflects the hormonal status of the neoplasm

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