scholarly journals Two Distinctive POMC Promoters Modify Gene Expression in Cushing’s Disease

2021 ◽  
Author(s):  
Takako Araki ◽  
Yukiko Tone ◽  
Masaaki Yamamoto ◽  
Hiraku Kameda ◽  
Anat Ben-Shlomo ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Methylation Status ◽  
Regulatory Region ◽  
Pituitary Tumors ◽  
Cushing's Disease ◽  
Human Pituitary ◽  
Ectopic Acth ◽  
Pomc Gene ◽  
Acth Secreting

Abstract Context Mechanisms underlying pituitary corticotroph adenoma ACTH production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. Objective We characterized the 5’ ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. Methods We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent pituitary corticotroph adenomas (SCA) that immunostain for but do not secrete ACTH. Results We identified a novel regulatory region located near the intron2/exon3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCA, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the USP8 mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing’s disease. Conclusion We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

scholarly journals Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

2015 ◽  
Vol 173 (4) ◽  
pp. M73-M83 ◽  
Author(s):  
Marily Theodoropoulou ◽  
Martin Reincke ◽  
Martin Fassnacht ◽  
Masayuki Komada
Keyword(s):  
Cushing’S Disease ◽  
Growth Factor Receptor ◽  
Pituitary Tumors ◽  
Cushing's Disease ◽  
Tumor Subtypes ◽  
Important Regulator ◽  
Epidermal Growth ◽  
Acth Secreting

Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.

TISSUE CULTURE STUDIES ON HUMAN PITUITARY TUMOURS: RADIOIMMUNOASSAYABLE ANTERIOR PITUITARY HORMONES IN THE CULTURE MEDIUM

1978 ◽  
Vol 88 (2) ◽  
pp. 239-249 ◽  
Author(s):  
Loren G. Lipson ◽  
Inese Z. Beitins ◽  
Paul D. Kornblith ◽  
Janet W. Mc Arthur ◽  
Henry G. Friesen ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Cushing’S Disease ◽  
Anterior Pituitary ◽  
Pituitary Hormones ◽  
Cushing's Disease ◽  
Hormone Release ◽  
Pituitary Tumours ◽  
Human Pituitary ◽  
Anterior Pituitary Hormones

ABSTRACT A tissue culture study was undertaken to determine if human non-functioning pituitary tumours secrete polypeptide anterior pituitary hormones in vitro and to study the spectrum of hormone release by functioning pituitary neoplasms. Fragments from 48 human pituitary tumours (from patients - 2 with Cushing's disease, 1 with Nelson's syndrome, 5 with amenorrhoea-galactorrhoea, 10 with acromegaly and 30 with non-functioning pituitary tumours) and three normal human anterior pituitary glands (controls) were placed in tissue culture immediately after surgery. The in vitro release of human growth hormone (HGH), prolactin (Prl), thyrotrophin (TSH), adrenocorticotrophin (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured by radioimmunoassays at the end of one week in culture. Clinical and pathological data were compared to hormone release patterns. In the culture media from control pituitaries the concentrations of the six hormones tested were 100 to 10 000 times greater than in peripheral blood. The medium surrounding the fragments from functioning pituitary tumours contained the following: a) Acromegaly - high levels of HGH and variable concentrations of the other hormones. b) Cushing's disease - ACTH and Prl predominantly. c) Amenorrhcea-galactorrhoea syndrome - prolactin in 4 out of 5 patients, all six polypeptides in one patient. In the media from the 30 patients diagnosed as having non-functioning pituitary tumours, 60 % of the samples contained at least one hormone at a concentration similar to that of the controls and 100 % of the samples contained detectable quantities of at least one hormone.

Immunochistochemical characteristics of blood vessels in non-visualized and visualized on MRI pituitary adenoma in patients with Cushing’s disease

2016 ◽  
Vol 62 (5) ◽  
pp. 65-66
Author(s):  
Patimat M. Khandaeva ◽  
Iya A. Voronkova ◽  
Zhanna E. Belaya ◽  
Lyudmila Y. Rozhinskaya ◽  
Aleksandr V. Vorontsov ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Blood Vessels ◽  
Cushing’S Disease ◽  
Pituitary Tumor ◽  
Pituitary Tumors ◽  
Average Diameter ◽  
Cushing's Disease ◽  
Retrospective Evaluation ◽  
Acth Secreting ◽  
Microvessels Density

Backgraund. Regardless of improvements in MRI, up to 20% of ACTH-secreting pituitary tumors are only identified at surgical exploration.Aim: to estimate whether there is any difference in blood vessels and the subsequent ability to uptake contrast agent in visualized microadenoma as compared to non-visualized on MRI ACTH-secreting pituitary tumors.Materials and methods. retrospective evaluation of ACTH-positive pituitary tumors from patients with Cushing’s disease (n=39) with either non-visualized pituitary tumor on MRI (n=17) or pituitary tumor less then 25 mm (n=22). MRI was performed using Siemens Magnetom Harmony 1.0T with gadolinium. Selected tumors were stained with anty-СD34 antibody (clone QBEnd/10, RTU, Leica) and anty-D2-40 antibody (clone D2-40, RTU, Dako). We evaluated the microvessels density and measured the diameter of larger and smaller vessel.Results. The microvessels density were not different in subject with visualized (123 [77;136]) and non-visualized (112 [110,0;126,5]) pituitary adenomas as well as number of slit-shaped vessels (32 [5;50] in visualized vs 25 [5;50] in non-visualized pituitary adenoma). The diameter of these vessels also did not differ: the diameter of the largest vessels in patients without visualization 53 µm [32,5;63,5] vs 33 µm [30,0;51,5], the average diameter of the blood vessels 15 µm [14,5-26,0] against 13 µm [12;14].Conclusions. The diameter and microvessels density in ACTH-producing pituitary adenoma does not affect the visualization of adenoma on MRI in patients with Cushing 's disease.

Immunochistochemical characteristics of blood vessels in non-visualized and visualized on MRI pituitary adenoma in patients with Cushing’s disease

2016 ◽  
Vol 62 (4) ◽  
pp. 11-17
Author(s):  
Patimat M. Khandaeva ◽  
Ija А. Voronkova ◽  
Zhanna E. Belaya ◽  
Ljudmila Ya. Rozhinskaya ◽  
Aleksandr V. Vorontsov ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Blood Vessels ◽  
Cushing’S Disease ◽  
Pituitary Tumor ◽  
Pituitary Tumors ◽  
Average Diameter ◽  
Cushing's Disease ◽  
Retrospective Evaluation ◽  
Acth Secreting ◽  
Microvessels Density

Background. Regardless of improvements in MRI, up to 20% of ACTH-secreting pituitary tumors are only identified at surgical exploration. Aim. Тo estimate whether there is any difference in blood vessels and the subsequent ability to uptake contrast agent in visualized microadenoma as compared to non-visualized on MRI ACTH-secreting pituitary tumors.Material and methods. Retrospective evaluation of ACTH-positive pituitary tumors from patients with Cushing’s disease (n=39) with either non-visualized pituitary tumor on MRI (n=17) or pituitary tumor less then 25 mm (n=22). MRI was performed using Siemens Magnetom Harmony 1.0T with gadolinium. Selected tumors were stained with anty-СD34 antibody (clone QBEnd/10, RTU, Leica) and anty-D2-40 antibody (clone D2-40, RTU, Dako). We evaluated the microvessels density and measured the diameter of larger and smaller vessel.Results. The microvessels density were not different in subject with visualized [123 (77; 136)] and non-visualized [112 (110,0; 126,5)] pituitary adenomas as well as number of slit-shaped vessels [32 (5; 50) in visualized vs 25 (5; 50) in non-visualized pituitary adenoma]. The diameter of these vessels also did not differ: the diameter of the largest vessels in patients without visualization 53 µm (32,5; 63,5) vs 33 µm (30,0; 51,5) the average diameter of the blood vessels 15 µm (14,5—26,0) against 13 µm (12; 14).Conclusions. The diameter and microvessels density in ACTH-producing pituitary adenoma does not affect the visualization of adenoma on MRI in patients with Cushing ‘s disease.

scholarly journals Corticotrophin-releasing activity of desmopressin in Cushing's disease: lack of correlation between in vivo and in vitro responsiveness

2003 ◽  
Vol 177 (3) ◽  
pp. 373-379 ◽  
Author(s):  
F Pecori Giraldi ◽  
E Marini ◽  
E Torchiana ◽  
P Mortini ◽  
A Dubini ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Pituitary Adenomas ◽  
Receptor Gene ◽  
Normal Subjects ◽  
Cushing's Disease ◽  
Receptor Antagonists ◽  
Releasing Effect ◽  
Acth Secreting

Desmopressin (DDAVP), an arginine vasopressin analogue, markedly stimulates ACTH secretion in patients with Cushing's disease, in contrast to its minimal effect in normal subjects. However, little is known about the mechanisms underlying this action and it appeared to be of interest to evaluate the effect of DDAVP on ACTH-secreting pituitary adenomas in vitro, in comparison with its effect in the same patients in vivo. Pituitary adenomas from 14 patients with Cushing's disease were incubated with DDAVP, corticotrophin-releasing hormone (CRH) and DDAVP together with vasopressin receptor antagonists or CRH. Incubation with DDAVP induced a modest dose-dependent increase in ACTH concentrations which appeared maximal at 10 nM. CRH stimulated ACTH to a greater extent compared with DDAVP and potentiated the effect of DDAVP alone. The DDAVP-induced ACTH increase appeared blunted by vasopressin V(2) and V(3) receptor antagonists. V(3) receptor gene expression was detected by RT-PCR in all adenoma samples except for two which were not responsive to DDAVP in vitro but responsive to the peptide in vivo. Surprisingly, no difference in the in vitro ACTH secretory response was observed between in vivo DDAVP-responsive (ACTH peak>150% baseline) and -unresponsive (ACTH peak<120% baseline) patients, suggesting that the pituitary adenoma is not the sole mediator of the ACTH-releasing effect of DDAVP. In conclusion, the marked stimulatory effect of DDAVP observed in patients with Cushing's disease appears to be mainly dependent on an extrapituitary action, possibly the inhibition of a corticotrophin release-inhibitory factor.

Usefulness of inferior petrosal sinus venous endocrine markers in Cushing's disease

1988 ◽  
Vol 68 (2) ◽  
pp. 205-210 ◽  
Author(s):  
John Zovickian ◽  
Edward H. Oldfield ◽  
John L. Doppman ◽  
Gordon B. Cutler ◽  
D. Lynn Loriaux
Keyword(s):  
Cushing’S Disease ◽  
Venous Blood ◽  
Pituitary Hormones ◽  
Cushing's Disease ◽  
Ectopic Acth Syndrome ◽  
Inferior Petrosal Sinus ◽  
Ectopic Acth ◽  
Content Type ◽  
Acth Secreting ◽  
Fine Print

✓ Bilateral and simultaneous sampling of the inferior petrosal sinuses in patients with Cushing's disease has been used to establish the presence and laterality of adrenocorticotropic hormone (ACTH)-producing microad-enomas prior to transsphenoidal surgery. Successful preoperative lateralization depends upon equivalent dilution of pituitary venous blood on the two sides since samples which are diluted by unequal amounts of non-pituitary blood may lead to erroneous results. To assure valid sampling results, the use of other pituitary hormones, measured simultaneously, has been proposed to correct the ACTH concentrations from the inferior petrosal sinuses against unequal dilution by non-pituitary venous blood. This proposal presumes that ACTH-secreting microadenomas will not cause unequal delivery of the other pituitary hormones into the two inferior petrosal sinuses. The inferior petrosal sinus concentrations of prolactin (PRL), thyrotropin (TSH), and the alpha subunit of human chorionic gonadotropin (α-HCG) were evaluated as indicators of pituitary venous blood dilution in 11 patients with Cushing's disease. Four patients with ectopic ACTH syndrome served as controls. Blood was withdrawn simultaneously from catheters in both inferior petrosal sinuses and from a peripheral vein for measurement of ACTH, PRL, TSH, and α-HCG. The ACTH concentrations were then corrected for dilution by non-pituitary blood by dividing the ACTH concentration from each side by the ratio of the inferior petrosal sinus to peripheral blood concentrations of PRL, TSH, and α-HCG for that side. At surgery, all 11 patients had ACTH-secreting microadenomas on the side predicted by the uncorrected ACTH concentrations. However, in three patients the corrected ACTH values would have led to erroneous results. Among the 18 sets of corrected inferior petrosal sinus measurements in these three patients, the corrected ACTH values failed to show an inferior petrosal sinus gradient in six and localized the tumor to the side opposite the adenoma in four. Incorrect lateralization was obtained with each of the hormones (PRL, TSH, and α-HCG) used for correction. Furthermore, the ipsilateral (side of tumor)-to-contralateral inferior petrosal sinus gradient of ACTH in patients with Cushing's disease was generally paralleled by a significant inferior petrosal sinus gradient of PRL, TSH, and α-HCG to the side of the tumor, whereas patients with the ectopic ACTH syndrome tended not to exhibit lateralizing (side-to-side) gradients. These findings indicate that the simultaneous measurement of inferior petrosal sinus concentrations of PRL or TSH or of the glycoprotein hormone α subunit does not improve preoperative localization of ACTH-secreting microadenomas and may lead to incorrect lateralization of the tumor. The results also suggest that ACTH-secreting microadenomas cause enhanced delivery of PRL, TSH, and α subunit into the inferior petrosal sinus ipsilateral to the tumor which, in turn, may reflect paracrine stimulation of hormone secretion in the anterior pituitary gland surrounding ACTH-secreting microadenomas.

scholarly journals MON-176 Discovery and Identification of Late Stage Selective Nonpeptide ACTH Antagonists for the Treatment of Cushing’s Disease, Ectopic ACTH Secreting Tumors, and Congenital Adrenal Hyperplasia

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ana Karin Kusnetzow ◽  
Sangdon Han ◽  
Melissa A Fowler ◽  
Jon Athanacio ◽  
Greg Reinhart ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adrenal Gland ◽  
Congenital Adrenal Hyperplasia ◽  
Cushing’S Disease ◽  
Cushing's Disease ◽  
High Morbidity ◽  
Adrenal Hyperplasia ◽  
Steroid Synthesis ◽  
Ectopic Acth ◽  
Acth Secreting

Abstract Adrenocorticotropic hormone (ACTH) is an important modulator of steroidal hormone synthesis and secretion from the adrenal gland and its selective activity at the melanocortin type 2 receptor (MC2) dictates the synthesis and secretion of cortisol (corticosterone in rats). Excess ACTH action contribute to the pathophysiology of Cushing’s disease (CD), ectopic ACTH secreting tumors (EAS), and Congenital Adrenal Hyperplasia (CAH). Cushing’s disease results from a microadenoma derived from pituitary corticotrophic cells that secretes excess ACTH, whereas EAS arises from nonpituitary ACTH secreting tumors. Excess ACTH action at the adrenal gland and resulting hypercortisolemia presents in a myriad of symptoms that result in high morbidity. CAH results from inactivating mutations in steroid synthesis pathways, resulting in lack of cortisol and aldosterone production. Lack of negative feedback by cortisol at the level of the pituitary causes the over-secretion of ACTH, and overproduction of adrenal androgens, causing significant virilization and reduction in quality of life. We hypothesize that blocking ACTH action directly via a selective MC2 receptor antagonist may provide an important new therapeutic mechanism for these patients. To test this hypothesis, Crinetics launched an iterative medicinal chemistry program to identify potent and selective nonpeptide ACTH antagonists with pharmaceutical and safety characteristics suitable for evaluation in human clinical trials. Unlike most other G protein coupled receptors, MC2 requires the presence of an accessory protein (MRAP) for cell surface expression and recognition of ACTH. Using CHO-K cells stably expressing this MC2-MRAP complex, iterative optimization led to the discovery of multiple chemical classes of highly potent, nonpeptide MC2 receptor selective antagonist leads, which were then further optimized for drug-like characteristics. We identified multiple compounds that exhibit high potency for human and rat MC2 receptors (hMC2 Kb &lt;1 nM), while having no activity at the MC1, MC3, MC4, or MC5 receptors. Leading ACTH antagonists were also evaluated for drug like characteristics, including good stability in liver microsomes, lack of inhibition of cytochromes P450 and the hERG ion channel, and were shown to exhibit good exposure upon oral dosing in both rats and dogs. These ACTH antagonists acutely suppress corticosterone secretion in an ACTH-challenge model in rats. In a 7-day hypercortisolemia model in which rats receive an implanted minipump that continually secretes ACTH, corticosterone levels were decreased, and body weight loss and adrenal hypertrophy were prevented with ACTH antagonist treatment. The culmination of these studies has led to a subset of candidate molecules that are being evaluated in genotoxicity, safety pharmacology, and general toxicology studies to enable evaluation in human clinical trials.

In Vitro Secretion of Adenoma and Anterior Lobe Cells in Two Typical Cases of Cushing's Disease

Neurosurgery ◽  
1983 ◽  
Vol 12 (5) ◽  
pp. 549-554 ◽  
Author(s):  
Dieter K. Lüdecke ◽  
Martin Schabet ◽  
Wolfgang Saeger
Keyword(s):  
Cushing’S Disease ◽  
Anterior Lobe ◽  
Cushing's Disease ◽  
Acth Secretion ◽  
Acth Cell ◽  
Superfusion System ◽  
Adenomatous Tissue ◽  
Corticoid Feedback ◽  
Acth Secreting

Abstract Fragments of adrenocorticotropic hormone (ACTH) cell adenomas and anterior lobes of two patients with Cushing's disease were obtained by transnasal operation. Both patients showed the typical clinical course, with postoperative ACTH deficit and all other pituitary functions intact. Equivalent specimens of tissue were investigated by immunocytology and in a superfusion system. The majority of adenoma cells were ACTH-positive, whereas ACTH-secreting cells of the anterior lobes were mostly inactive and were reduced in number. In vitro, adenomatous tissue showed high ACTH secretion into the superfusion medium, which was increased significantly after vasopressin application. Corticoid feedback was impaired. Anterior lobe cells exhibited a significant spontaneous ACTH secretion that was reduced by cortisol, but not stimulated by vasopressin. These results support the concept of an impaired corticoid feedback at the adenoma level in the presence of suppressed ACTH secretion of the para-adenomatous anterior lobe.

Phosphorylated forms of adrenocorticotropin and corticotropin-like intermediary lobe peptide in human tumors

1994 ◽  
Vol 131 (4) ◽  
pp. 341-346 ◽  
Author(s):  
Jean Francis Massias ◽  
Sandrine Hardouin ◽  
Didier Vieau ◽  
Frédéric Lenne ◽  
Xavier Bertagna
Keyword(s):  
Cushing’S Disease ◽  
Pituitary Tumors ◽  
Human Tumors ◽  
Cushing's Disease ◽  
Ectopic Acth Syndrome ◽  
Ectopic Acth ◽  
Port Royal ◽  
Phosphatase Treatment ◽  
Highperformance Liquid Chromatography ◽  
Set Up

Massias JF, Hardouin S, Vieau D, Lenne F, Bertagna X. Phosphorylated forms of adrenocorticotropin and corticotropin-like intermediary lobe peptide in human tumors. Eur J Endocrinol 1994;131:341–6. ISSN 0804–4643 Many peptides contribute to the heterogeneity of immunoreactive adrenocorticotropin (ACTH) in man. The use of a radioimmunoassay (RIA) specifically directed against the C-terminal end of ACTH allowed us to study precisely the following four peptides: ACTH itself, corticotropin-like intermediary lobe peptide (CLIP) or ACTH(18–39) and their phosphorylated forms on Ser31. We have set up a highperformance liquid chromatography system that separates these four molecules in a single run, to establish their relative distributions in tumors responsible for Cushing's disease or for the ectopic ACTH syndrome, and to evaluate the possible interference of phospho-Ser on various RIA or immunoradiometric assay (IRMA) recognition systems for ACTH. In this system, alkaline phosphatase treatment shifted the retention time of the phosphorylated peptides to that of their non-phosphorylated counterparts. In three tumors responsible for the ectopic ACTH syndrome, CLIP peptides were predominant in two and phosphorylated molecules represented between 22% and 50% of immunoreactive materials. In five pituitary tumors responsible for Cushing's disease, ACTH peptides were predominant and the phosphorylated molecules varied between 35% and 75% in four of them. In the same tumor the ratios of phosphorylated to non-phosphorylated CLIP or ACTH were identical. The presence of phospho-Ser31 did not affect the recognition ability of two mid-ACTH and two C-terminal ACTH RIAs, nor of the ACTH IRMA (Allegro, Nichols). Xavier Bertagna, CJF 92-08 Endocrinologie, Faculté Cochin-Port Royal, 24 rue du Faubourg Saint Jacques, 75014 Paris, France

Pro-opiomelanocortin mRNA size heterogeneity in ACTH-dependent Cushing's syndrome

1989 ◽  
Vol 2 (1) ◽  
pp. 3-9 ◽  
Author(s):  
A. J. L. Clark ◽  
P. M. Lavender ◽  
G. M. Besser ◽  
L. H. Rees
Keyword(s):  
Human Pituitary ◽  
Ectopic Acth ◽  
S1 Nuclease ◽  
Pomc Mrna ◽  
Mrna Content ◽  
Normal Human ◽  
Pomc Gene ◽  
Low Levels ◽  
Size Heterogeneity ◽  
Acth Secreting

ABSTRACT As an approach to understanding the abnormalities of pro-opiomelanocortin (POMC) gene regulation in human ACTH-secreting tumours, we have analysed the POMC mRNA content of nine such tumours using the Northern blot technique. Most of the tumours and normal human pituitary contained easily detectable quantities of POMC mRNA. The length of this message in most tumours was similar to, or slightly larger than, that in the normal pituitary (1150–1200 bases). Ribonuclease H studies suggested that the origin of any size heterogeneity was a longer poly(A) tail in the tumour RNA. Some tumours, however, expressed a short POMC mRNA (800 bases) which may lack the first two exons of the POMC gene as has been described. A third POMC mRNA size variant (1500 bases) was also seen in low levels in two cases, and as the principal mRNA species in one case. Primer extension and S1 nuclease protection studies suggested that most transcripts in the tumours analysed originated from the conventional promoter, and thus the use of an alternative promoter is not an adequate explanation for the expression of this gene in ectopic ACTH-secreting tumours.

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