help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Reincke, M.
Right arrow Articles by Allolio, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reincke, M.
Right arrow Articles by Allolio, B.
The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 3054-3058
Copyright © 1997 by The Endocrine Society

Original Studies

Deletion of the Adrenocorticotropin Receptor Gene in Human Adrenocortical Tumors: Implications for Tumorigenesis1

Martin Reincke, Patricia Mora, Felix Beuschlein, Wiebke Arlt, George P. Chrousos and Bruno Allolio

Department of Internal Medicine, University of Wurzburg, Wurzburg, Germany; and the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (G.P.C.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: PD Dr. Martin Reincke, Schwerpunkt Endokrinologie, Medizinische Universitätsklinik Würzburg, Josef-Schneider-Strasse 2, 97080 Wurzburg, Germany.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Constitutive activating mutations of G protein-coupled receptors, such as that of TSH, have been implicated in the tumorigenesis of human endocrine neoplasms, such as thyroid adenomas. In a previous study we reported that constitutive activating point mutations of the ACTH receptor (ACTH-R) gene, a member of the G protein-coupled receptor superfamily, were not present in hormone-secreting and nonsecretory adrenocortical neoplasms. In this study, we investigated whether allelic loss of the ACTH-R gene is present in sporadic adrenal tumors. We identified a PstI polymorphism in the promoter region 3 kilobases upstream of the coding region of the ACTH-R gene. The rate of heterozygosity for this polymorphism in 99 unrelated Caucasian individuals was 53.5%. Using this polymorphism, we analyzed loss of heterozygosity (LOH) of the ACTH-R gene in 20 informative cases with benign and malignant adrenocortical tumors. Of 16 patients with benign lesions, LOH was present in 1 oncocytic nonfunctional adenoma, but not in 15 hyperfunctioning adenomas. Of 4 informative patients with adrenocortical carcinomas, LOH was present in 2 cases. Both patients had advanced tumor stages and showed a more rapid course than carcinoma patients without LOH. Analysis of the flanking region of the ACTH-R using the polymorphic microsatelite marker D18S37 and D18S40 showed that this deletion was confined to the ACTH-R gene. Northern blot experiments demonstrated reduced expression of ACTH-R messenger ribonucleic acid in the tumors with LOH of the ACTH-R gene, suggesting functional significance of this finding at the transcriptional level. We conclude that LOH of the ACTH-R gene is possibly involved in adrenal tumorigenesis, contributing to cellular dedifferentiation in adenomas and carcinomas.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADRENOCORTICAL carcinoma is a rare, highly malignant tumor with an incidence of 1.7/million. In contrast, benign adrenocortical lesions are very frequent (prevalence, 1/100). Most of these tumors are detected incidentally by ultrasound or computed tomography (so-called incidentalomas) (1). Histopathological differentiation of benign from malignant adrenocortical lesions is crucial for treatment and follow-up. However, histopathological classification of adrenocortical carcinomas can be difficult if metastases or infiltration of surrounding tissues are absent, especially in small, well differentiated carcinomas (2, 3).

The human ACTH receptor (ACTH-R) is a member of the G protein-coupled seven-transmembrane domain superfamily of receptors and belongs, together with several MSH receptors, to the melanocortin receptor family (4, 5). The ACTH-R gene was recently cloned (4) and mapped on chromosome 18p11.2 (6, 7). In a previous study, we reported that no constitutive activating point mutations of the ACTH-R gene were present in adrenocortical neoplasms, in contrast to earlier findings of activating mutations of the TSH receptor in thyroid adenomas (8). These data and evidence from in vitro experiments (9) suggested that ACTH was a differentiating factor of the adrenal cortex, with a low potential of stimulating cell proliferation and tumorigenesis. Thus, inactivation of the ACTH-R signal transduction cascade could result in loss of differentiation and enhanced clonal expansion of adrenal tumors.

We recently identified a PstI polymorphism located approximately 3 kilobases (kb) upstream of the ACTH-R-coding region (10). Using this polymorphism, we investigated whether allelic loss of the ACTH receptor gene occurs in adrenocortical neoplasms. We herein report that deletion of the ACTH-R gene at 18p11.2 is present in a subset of adrenocortical neoplasms characterized by loss of differentiation and/or aggressive growth.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Normal subjects and patients

Blood was collected from 99 unrelated Caucasian individuals (57 females and 42 males) after giving written informed consent and stored at -80 C until DNA extraction.

Forty-one patients with a variety of adrenal diseases were studied. Twenty of these (49%) were heterozygous for the PstI polymorphism of the ACTH-R gene. The clinical data for these patients are shown in Tables 1Go and 2Go. The clinical and pathological diagnosis was made according to established criteria (2, 3, 11, 12). Blood and neoplastic adrenal tissue was collected with the approval of the ethical committee of the University Hospital of Wurzburg. Normal adult adrenals (n = 4) were obtained after organs were removed from brain-dead patients for transplantation. After removing adjacent fat tissue, the tissues were snap-frozen and immediately stored at -80 C until analyzed.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical data of the 16 adenoma patients informative for the PstI polymorphism in the ACTH receptor gene

 

View this table:
[in this window]
[in a new window]
  		Table 2. Clinical data of the patients with adrenal carcinomas informative for the PstI polymorphism in the ACTH receptor gene

 
Southern blot

The PstI polymorphism used in this study is located upstream of the ACTH-R gene (Fig. 1Go). It was detected when DNA was double digested with PstI and MspI/HpaII to study the methylation pattern of the ACTH-R gene in adrenocortical tumors. Digestion with other restriction enzymes and hybridization with different ACTH-R complementary DNA (cDNA) fragments showed that the polymorphism is located 3.1 kb upstream of the ACTH receptor-coding region, within the ACTH-R promoter (data not shown). Leukocytic or tumor DNA was extracted by means of proteinase K digestion and phenol/chloroform extraction. After digestion with PstI according to the instructions of the manufacturer (Boehringer Mannheim, Mannheim, Germany), the DNA was electrophoresed through a 0.8% agarose gel and blotted onto a nylon membrane (Amersham, Braunschweig, Germany). Hybridization was performed using an [{alpha}-32P]CTP (Amersham)-labeled (Random Primed Labeling Kit, Boehringer Mannheim) full-length human ACTH-R cDNA (a 1061-bp fragment of the human ACTH-R generated by PCR using human genomic DNA as template and 5'-GAT TTA ACT TAG ATC TCC AGC AAG T-3' and 5'-CGT TGC CAA GTG CCA GAA TAG TGT-3' as upstream and downstream primers, respectively (4). Heterozygous individuals showed two bands of 4.5 and 4 kb.



View larger version (11K):
[in this window]
[in a new window]
  		Figure 1. Restriction map of the ACTH-R gene. 1, Nontranslated exon approximately 10 kb upstream of the ACTH-R coding region (19); 2, ACTH-R-coding region.

 
Using the polymorphic microsatelite markers D18S37 and D18S40 (13, 14) on the short arm of chromosome 18 close to the ACTH-R gene (14), we delineated the extent of the deletion of the ACTH-R gene. One of the primers was end labeled with [{gamma}-32P]ATP, and PCR of leukocytic and tumor DNA was performed as described previously (13).

PCR and direct sequencing of the ACTH-R gene

In all patients informative for the PstI polymorphism, the ACTH-R gene-coding region was amplified using the PCR and directly sequenced by the dideoxy nucleotide chain termination method, using modified T7-DNA polymerase (Sequenase, U.S. Biochemical Corp., Cleveland, OH) in the presence of [{alpha}-35S]deoxy-ATP, as described previously (8).

Northern blot

Total or polyadenylated ribonucleic acid (RNA) was isolated from tissue using the guanitidin isocyanate method (Stratagene, Heidelberg, Germany). The RNA integrity was checked by ethidium bromide stain, and degraded RNA samples were excluded. The RNA was directly dot blotted on a nylon membrane. Hybridization was performed using the same probe as that for a Southern blot (15). For standardization, the blots were hybridized with a mouse ß-actin cDNA probe. The steady state messenger RNA (mRNA) concentrations are expressed as a percentage of that in normal adrenals (=100%). Autoradiographic images were digitalized with a video camera and a Macintosh PowerMac 7100 computer-based image analysis system (Stemmer, Puchheim, Germany) using the IMAGE program (NIMH, NIH, Bethesda, MD).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Rate of heterozygosity in normal subjects

Fifty-three of the 99 normal subjects (53.5%) were heterozygous for the PstI polymorphism (Fig. 2Go).



View larger version (61K):
[in this window]
[in a new window]
  		Figure 2. PstI polymorphism of the ACTH-R gene in six normal subjects. Heterozygote individuals (lanes 1, 4, and 5) are informative for LOH analysis.

 
Loss of heterozygosity (LOH) in adrenocortical adenomas

Of 16 patients with adrenocortical adenomas informative for the PstI polymorphism (15 functional and 1 nonfunctional adenoma), only the patient with a large nonfunctional adenoma demonstrated LOH of the ACTH-R gene in the tumor tissue (Table 1Go and Fig. 3Go). This tumor was incidentally detected by computed tomography and measured 7 cm in maximum diameter. The patient was clinically asymptomatic and had normal serum potassium levels, normal PRA, and normal suppression of serum cortisol by 2 mg dexamethasone. Surgery was suggested because of its size to exclude adrenocortical carcinoma, and the patient underwent adrenalectomy with uneventful recovery. Histopathology showed an oncocytic (0 cell) adrenal adenoma composed of large tumor cells with abundant eosinophilic cytoplasm. The patient has remained in remission, and follow-up studies have been negative for tumor recurrence.



View larger version (31K):
[in this window]
[in a new window]
  		Figure 3. LOH of the ACTH-R gene. Leukocytic (L) and tumor (Tu) DNA were digested, electrophorised, and hybridized, as described in Subjects and Methods. Center and right, Two tumors with LOH at the PstI restriction site. Left, Adrenal adenoma without LOH.

 
LOH in adrenocortical carcinomas

Two of four patients with adrenocortical carcinomas had LOH of the ACTH-R gene. Clinical presentation, tumor stage, and disease-free survival of these patients are shown in Table 2Go. Compared to patients with adrenocortical carcinomas without LOH, patients with LOH of the ACTH-R gene had advanced tumor stages, early recurrence, and/or a more rapid course.

Polymorphic microsatelite markers D18S37 and D18S40

All patients were informative for at least one of the microsatelite markers, D18S37 and D18S40. Neither the 3 tumors with LOH of the ACTH-R gene locus nor the 17 tumors without LOH of the ACTH-R gene locus showed LOH using the D18537 or D18540 markers, demonstrating that the deletion was confined to the ACTH-R gene locus.

PCR amplification and sequencing of the ACTH-R gene

Using PCR, we amplified the coding region of the ACTH-R gene of DNA from all tumor tissues. Direct sequencing of the PCR products revealed no point mutations or small deletions in the entire ACTH receptor sequence.

ACTH-R mRNA expression

Expression of ACTH-R mRNA was analyzed by Northern and dot blot experiments in 17 of the 20 tumor tissues available for RNA extraction. Compared to normal adrenals (100 ± 12%) and adrenocortical tumors without LOH of the ACTH-R gene (102 ± 20%), tumors with LOH showed greatly reduced ACTH-R mRNA steady state concentrations (21 ± 4%; Figs. 4Go and 5Go).



View larger version (94K):
[in this window]
[in a new window]
  		Figure 4. ACTH-R mRNA expression in adrenocortical tumors assessed by dot blot. Polyadenylated mRNA was hybridized with a 32P-labeled full-length ACTH-R cDNA (top) and a mouse ß-actin cDNA (bottom). Row 1, Two normal adrenals; row 2, two tumors with LOH at the PstI polymorphism; row 3, tumors without LOH (aldosterone-producing adenomas).

 


View larger version (26K):
[in this window]
[in a new window]
  		Figure 5. ACTH-R mRNA expression (mean ± SEM) in normal adrenals, tumors without LOH of the ACTH-R gene, and tumors with LOH.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
cAMP is a key second messenger involved in hormone hypersecretion and/or increased cell proliferation in a variety of endocrine tissues. Oncogenic transformation by constitutive activation of key regulatory proteins of cAMP, such as G protein-coupled receptors and GTP-binding proteins, have been implicated in the pathogenesis of such diseases as acromegaly and toxic thyroid adenomas (16, 17). Adrenocortical tumorigenesis differs from pituitary and thyroid tumorigenesis, as activation of the cAMP/protein kinase A pathway seems to be of little importance in the development of adrenocortical neoplasms. ACTH is the main hormone regulating steroid hormone secretion; however, it fails to cause adrenocortical hypertrophy in the absence of innervation by the splanchnic nerve. ACTH in physiological concentrations does not stimulate cell proliferation of adrenocortical cells in vitro, and even pharmacological doses of ACTH induce only moderate cell growth (9). In keeping with these findings, activating mutations of neither the ACTH receptor nor the {alpha}-chain of the Gs have been identified in benign or malignant adrenocortical tumors (8, 16). On the contrary, activating mutations of the Gi2, one of the adenylyl cyclase inhibitory G proteins, were found in very few adrenocortical tumors, but not in a variety of other endocrine and nonendocrine tumors (16, 18). These data suggest that in the adrenal cortex the ACTH/Gs/protein kinase A signaling pathway is preferentially important for steroid hormone secretion and, hence, for maintenance of a highly differentiated cellular phenotype, but is of relatively little importance for cellular proliferation. Mutational loss of the ACTH-R gene by deletion, therefore, could result in loss of differentiation, a characteristic feature of human tumorigenesis that is associated with clonal expansion of a malignant cell clone. We herein demonstrate for the first time that allelic loss of a gene for a G protein-coupled receptor, that of the ACTH-R, is present in a subset of adrenocortical tumors, suggesting implications for the pathogenesis of these tumors. Three of 20 tumors in our series showed LOH for a PstI polymorphism in the promoter of the ACTH-R gene, suggesting a deletion within the promoter and/or the ACTH-R gene itself. The specificity of the ACTH-R deletion is supported by the data generated using the microsatelite markers D18S37 and D18S40, located 9.4 and 3.2 centimorgans upstream of the ACTH-R (13, 19), respectively, which did not reveal LOH at these loci. The functional significance of our findings at the transcriptional level is supported by reduced steady state concentrations of ACTH-R mRNA found in these tumors compared to those in normal adrenals and adrenocortical tumors without LOH of the ACTH-R gene. One of 16 benign lesions in this study demonstrated LOH of the ACTH-R gene locus. This tumor differed from the other 15 adenomas in size, steroid activity, and histopathology. It was clinically and biochemically nonfunctional, in contrast to adenomas without LOH of the ACTH-R, which were all hyperfunctioning aldosterone- or cortisol-producing adenomas. Histopathology demonstrated an oncocytic adenoma. Oncocytic adrenal cortical neoplasms are a rare variant of adrenocortical tumors characterized by large tumor cells with abundant finely granular eosinophilic cytoplasm filled with mitochondria (20, 21). Oncocytic changes can also be found in adrenocortical carcinomas (22), and close postoperative follow-up is required in patients with oncocytic tumors because of their potentially malignant behavior (20).

Two of four adrenocortical carcinomas showed LOH of the ACTH-R gene. The patients with carcinomas with LOH had advanced tumor stages, aggressive tumor growth, early recurrence after adrenalectomy, and an unfavorable outcome. This indicates that deletions of the ACTH-R gene in adrenocortical carcinomas are associated with clonal expansion of undifferentiated and/or highly malignant tumor clones. LOH and microsatellite instability are important characteristics of many tumor types. These DNA deletions affect chromosomal areas of known or supposed tumor suppressor genes. Functional inactivation of the other allele of a tumor suppressor gene occurs generally by missense point mutations eliminating all wild-type tumor suppressor activity and enhancing clonal expansion of a malignant cell clone. LOH of the ACTH-R gene at 18p11.2 suggests that the ACTH-R may act as a tumor suppressor gene in adrenocortical tumorigenesis. The clinical features of tumors with LOH in our series (loss of steroidogenesis in the oncocytoma, aggressive growth in adrenal carcinomas) is in accordance with this idea. We were not able to detect inactivating point mutations in the remaining ACTH-R allele. However, this does not necessarily exclude inactivation of the other allele, as mutations outside of the coding region, such as in the ACTH-R promoter, may have been missed by our approach. Evidence for functional inactivation of the ACTH-R by means other than mutations comes from the mouse adrenocortical tumor cell line Y1. In this cell line, ACTH and compounds such as the long-acting cAMP analog 8-bromo-cAMP stimulate steroidogenesis but inhibit cell proliferation (23). Schimmer et al. (24) reported two mutant subclones, Y6 and OS3, that do not express functional ACTH receptors, in contrast to the ACTH-sensitive parental cell line Y1. The ACTH-R gene transcription in these subclones is completely silenced by mechanisms not involving deletions or altered methylation of the ACTH-R gene. These data show that inactivation of the ACTH receptor can also be caused by as yet unidentified transcription factors and cis-acting DNA promoter elements. Alternatively, deletion of one ACTH-R allele could be sufficient for oncogenic transformation, as has been suggested for other tumor suppressor genes. For example, mutations of the p53 tumor suppressor gene located at chromosome 17p affect only one allele in certain tumor types, such as basal cell carcinoma (25) and adrenocortical tumors (26). This can be explained by a dominant negative effect or a gain of function of the mutant p53 protein.

In summary, LOH of the ACTH-R gene and low expression of ACTH-R mRNA are present in a subset of adrenocortical tumors that were either nonfunctional or highly malignant. These data suggest that deletion of a G-coupled receptor may give tumors a growth advantage. Under physiological circumstances, the ACTH-R-cAMP-protein kinase A signaling cascade maintains a differentiated adrenocortical cell phenotype, whereas proliferation of adrenocortical cells is stimulated mainly by peptides and receptors other than ACTH and its receptor. Partial deletion of the ACTH-R gene could, therefore, result in loss of differentiation and stimulation of a growth path.


   Footnotes
 
1 This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Re 752/5–1). Back

Received February 26, 1997.

Revised May 13, 1997.

Accepted May 21, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Ross NS, Aron DC. 1990 Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med. 323:1401–1405.[Medline]
  2. Hough AJ, Hollifield JW, Page DL, et al. 1979 Prognosis factors in adrenocortical tumors. Am J Clin Pathol. 72:390–399.[Medline]
  3. Weiss LM. 1984 Comparative histologic study of 43 metastasing and nonmetastasing adrenocortical tumors. Am J Pathol. 8:163–169.
  4. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. 1992 The cloning of a family of genes that encode the melanocortin receptors. Science. 275:1248–1251.
  5. Siegrist W, Eberle AN. 1995 Melanocortins and their implication in melanoma. Trends Endocrinol Metab. 6:115–120.
  6. Gantz I, Tashiro T, Barcroft C, et al. 1993 Localization of the genes encoding the melanocortin-2 (ACTH hormone) and melanocortin-3 receptors to chromosome 18p11.2 and 20.q13.2–13.3 by fluorecent in situ hybridization. Genomics. 18:166–167.[CrossRef][Medline]
  7. Vamvakopoulos NC, Durkin S, Nierman W, Chrousos GP. 1993 Mapping the human adrenocorticotropin receptor gene to the small arm of chromosome 18 (18p.11.21-pter). Genomics. 18:454–455.[CrossRef][Medline]
  8. Latronico AC, Reincke M, Mendonca BB, et al. 1995 No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms. J Clin Endocrinol Metab. 80:875–877.[Abstract]
  9. Estivariz FE, Iturriza F, Mclean C, Hope J, Lowry PJ. 1982 Stimulation of adrenal mitogenesis by N-terminal proopiomelanocortin. Nature. 297:419–422.[CrossRef][Medline]
  10. Reincke M, Mora P, Beuschlein B, Lehmann R, Karl M, Allolio B. 1995 No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms. Exp Clin Endocrinol. 103(Suppl 1):129.
  11. Baxter JD, Tyrrel JB. 1986 The adrenal cortex. In: Felig P, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and metabolism, 2nd ed. New York: McGraw-Hill; 511–692.
  12. Orth DN, Kovacs WJ, DeBold CR. 1992 The adrenal cortex. In: Wilson JD, Foster DW, eds. Williams textbook of endocrinology, 8th ed. Philadelphia: Saunders; 489–621.
  13. Berrettini WH, Ferraro TN, Goldin LR, et al. 1994 Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene. Proc Natl Acad Sci USA. 91:5918–5921.[Abstract/Free Full Text]
  14. Detera-Wadleigh SD, Yoon SW, Berrettini WH, et al. 1995 ACTH receptor/melanocortin receptor-2 maps within a reported susceptibility for bipolar illness on chromosome 18. Am J Med Genet. 60:317–321.[CrossRef][Medline]
  15. Reincke M, Beuschlein F, Menig G, et al. ACTH receptor mRNA expression in adrenocortical tumors: comparison with P450 steroidogenic enzyme expression. Clin Endocrinol (Oxf). 46:619–626.
  16. Lyons J, Landis CA, Harsh G, et al. 1990 Two G protein oncogenes in human endocrine tumors. Science. 249:655–659.[Abstract/Free Full Text]
  17. Parma J, Duprez L, Van Sande J, et al. 1993 Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature. 365:649–651.[CrossRef][Medline]
  18. Reincke M, Karl M, Travis W, Chrousos GP. 1993 No evidence for oncogenic mutations in guanine nucleotide binding proteins of human adrenocortical neoplasms. J Clin Endocrinol Metab. 77:1419–1422.[Abstract]
  19. Naville D, Barjhoux L, Jaillard C, Lebrethon MC, Saez JM, Begeot M. 1994 Characterization of the transcription start site of the ACTH receptor gene: presence of an intronic sequence in the 5'-flanking region. Mol Cell Endocrinol. 106:131–135.[CrossRef][Medline]
  20. Erlandson RA, Reuter VE. 1991 Oncocytic adrenal cortical adenoma. Ultrastruct Pathol. 15:539–547.[Medline]
  21. Mitchell A, Scheithauer BW, Sasano H, Hubbard EW, Ebersold MJ. 1993 Symptomatic intradural adrenal adenoma of the spinal nerve root: report of two cases. Neurosurgery. 32:658–661.[Medline]
  22. Mackay B, el-Naggar A, Ordonez NG. 1994 Ultrastructure of adrenal cortical carcinoma. Ultrastruct. Pathol. 18:181–190.
  23. Schimmer BP, Tsao J, Knapp M. 1977 Isolation of mutant adrenocortical tumor cells resistant to cyclic nucleotides. Mol Cell Endocrinol. 8:135–145.[CrossRef][Medline]
  24. Schimmer BP, Kwan WK, Tsao J, Qiu R. 1995 Adrenocorticotropin-resistant mutants of the Y1 adrenal cell line fail to express the ACTH receptor. J Cell Physiol. 163:164–171.[CrossRef][Medline]
  25. Van der Riet P, Karp D, Farmer E, et al. 1994 Progression of basal cell carcinoma through loss of chromosome 9q and inactivation of a single p53 allel. Cancer Res. 54:27–27.
  26. Lin SR, Lee YJ, Tsai JH. 1994 Mutations of the p53 gene in human functional neoplasms. J Clin Endocrinol Metab. 78:483–491.[Abstract]



This article has been cited by other articles:


Home page
 The OncologistHome page
P. S. H. Soon, K. L. McDonald, B. G. Robinson, and S. B. Sidhu
Molecular Markers and the Pathogenesis of Adrenocortical Cancer
Oncologist, May 1, 2008; 13(5): 548 - 561.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. S. Nadella, G. N. Jones, A. Trimboli, C. A. Stratakis, G. Leone, and L. S. Kirschner
Targeted Deletion of Prkar1a Reveals a Role for Protein Kinase A in Mesenchymal-to-Epithelial Transition
Cancer Res., April 15, 2008; 68(8): 2671 - 2677.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
R. Libe, A. Fratticci, and J. Bertherat
Adrenocortical cancer: pathophysiology and clinical management
Endocr. Relat. Cancer, March 1, 2007; 14(1): 13 - 28.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
R. Libe and J. Bertherat
Molecular genetics of adrenocortical tumours, from familial to sporadic diseases
Eur. J. Endocrinol., October 1, 2005; 153(4): 477 - 487.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
O. Zwermann, D. M Schulte, M. Reincke, and F. Beuschlein
ACTH 1-24 inhibits proliferation of adrenocortical tumors in vivo
Eur. J. Endocrinol., September 1, 2005; 153(3): 435 - 444.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. J. Betz, I. Shapiro, M. Fassnacht, S. Hahner, M. Reincke, F. Beuschlein, and for the German Austrian Adrenal Network
Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Suppress Adrenocortical Tumor Cell Proliferation and Induce Differentiation
J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3886 - 3896.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
O. Zwermann, F. Beuschlein, E. Lalli, A. Klink, P. Sassone-Corsi, and M. Reincke
Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression
Eur. J. Endocrinol., May 1, 2005; 152(5): 769 - 776.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
P. Ferruzzi, E. Ceni, M. Tarocchi, C. Grappone, S. Milani, A. Galli, G. Fiorelli, M. Serio, and M. Mannelli
Thiazolidinediones Inhibit Growth and Invasiveness of the Human Adrenocortical Cancer Cell Line H295R
J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1332 - 1339.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A.-M. Lefrancois-Martinez, J. Bertherat, P. Val, C. Tournaire, N. Gallo-Payet, D. Hyndman, G. Veyssiere, X. Bertagna, C. Jean, and A. Martinez
Decreased Expression of Cyclic Adenosine Monophosphate-Regulated Aldose Reductase (AKR1B1) Is Associated with Malignancy in Human Sporadic Adrenocortical Tumors
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3010 - 3019.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
P. Luciani, P. Ferruzzi, G. Arnaldi, C. Crescioli, S. Benvenuti, G. Nesi, A. Valeri, I. Greeve, M. Serio, M. Mannelli, et al.
Expression of the Novel Adrenocorticotropin-Responsive Gene Selective Alzheimer's Disease Indicator-1 in the Normal Adrenal Cortex and in Adrenocortical Adenomas and Carcinomas
J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1332 - 1339.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
D. Rosenberg, L. Groussin, E. Jullian, K. Perlemoine, S. Medjane, A. Louvel, X. Bertagna, and J. Bertherat
Transcription Factor 3',5'-Cyclic Adenosine 5'-Monophosphate-Responsive Element-Binding Protein (CREB) Is Decreased during Human Adrenal Cortex Tumorigenesis and Fetal Development
J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3958 - 3965.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. A. Koch, K. Pacak, and G. P. Chrousos
The Molecular Pathogenesis of Hereditary and Sporadic Adrenocortical and Adrenomedullary Tumors
J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5367 - 5384.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
F. M. Swords, A. Baig, D. M. Malchoff, C. D. Malchoff, M. O. Thorner, P. J. King, L. Hunyady, and A. J. L. Clark
Impaired Desensitization of a Mutant Adrenocorticotropin Receptor Associated with Apparent Constitutive Activity
Mol. Endocrinol., December 1, 2002; 16(12): 2746 - 2753.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Peri, P. Luciani, B. Conforti, S. Baglioni-Peri, F. Cioppi, C. Crescioli, P. Ferruzzi, S. Gelmini, G. Arnaldi, G. Nesi, et al.
Variable Expression of the Transcription Factors cAMP Response Element-Binding Protein and Inducible cAMP Early Repressor in the Normal Adrenal Cortex and in Adrenocortical Adenomas and Carcinomas
J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5443 - 5449.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
A. Lacroix, N. N'Diaye, J. Tremblay, and P. Hamet
Ectopic and Abnormal Hormone Receptors in Adrenal Cushing's Syndrome
Endocr. Rev., February 1, 2001; 22(1): 75 - 110.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
K.-M. Schulte, M. Mengel, M. Heinze, D. Simon, S. Scheuring, K. Köhrer, and H.-D. Röher
Complete Sequencing and Messenger Ribonucleic Acid Expression Analysis of the MEN I Gene in Adrenal Cancer
J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 441 - 448.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. Pilon, P. Mulatero, L. Barzon, F. Veglio, C. Garrone, M. Boscaro, N. Sonino, and F. Fallo
Mutations in CYP11B1 Gene Converting 11{beta}-Hydroxylase into an Aldosterone-Producing Enzyme Are Not Present in Aldosterone-Producing Adenomas
J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4228 - 4231.
[Abstract] [Full Text]

Home page
 Am. J. Pathol.Home page
J. Zhao, E. J. M. Speel, S. Muletta-Feurer, K. Rutimann, P. Saremaslani, J. Roth, P. U. Heitz, and P. Komminoth
Analysis of Genomic Alterations in Sporadic Adrenocortical Lesions : Gain of Chromosome 17 Is an Early Event in AdrenocorticalTumorigenesis
Am. J. Pathol., October 1, 1999; 155(4): 1039 - 1045.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
S. R. Bornstein, C. A. Stratakis, and G. P. Chrousos
Adrenocortical Tumors: Recent Advances in Basic Concepts and Clinical Management
Ann Intern Med, May 4, 1999; 130(9): 759 - 771.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Kjellman, L. Roshani, B. T. Teh, O.-P. Kallioniemi, A. Höög, S. Gray, L.-O. Farnebo, M. Holst, M. Bäckdahl, and C. Larsson
Genotyping of Adrenocortical Tumors: Very Frequent Deletions of the MEN1 Locus in 11q13 and of a 1-Centimorgan Region in 2p16
J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 730 - 735.
[Abstract] [Full Text]

Home page
 NEJMHome page
H. S. Willenberg, C. A. Stratakis, C. Marx, M. Ehrhart-Bornstein, G. P. Chrousos, and S. R. Bornstein
Aberrant Interleukin-1 Receptors in a Cortisol-Secreting Adrenal Adenoma Causing Cushing's Syndrome
N. Engl. J. Med., July 2, 1998; 339(1): 27 - 31.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Reincke, M.
Right arrow Articles by Allolio, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reincke, M.
Right arrow Articles by Allolio, B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals