The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease

Abstract :
Context: Cushing disease (CD) is due to pituitary corticotrope adenomas that produce unrestrained ACTH secretion and have lost the negative feedback exerted by glucocorticoids (GCs). GCs also restrain corticotrope proliferation, and the mechanisms of this inhibition are poorly understood.
Objective: The aim of the study was to identify cell cycle regulatory genes that are regulated by GCs and the glucocorticoid receptor and to assess regulatory genes that have a rate-limiting action on corticotrope proliferation and may be disregulated in CD.
Design: The mouse corticotrope tumor cells AtT-20 were used to identify GC-regulated genes that contribute to control of cell cycle progression. Surgery sections from patients with CD were used to assess expression of CABLES1 in corticotrope adenomas.
Methods: Gene expression profiling, small interfering RNA knockdowns, cell cycle analyses, and genetic manipulations were performed in AtT-20 cells. Sequencing of chromatin immunoprecipitation for pituitary-restricted transcription factors and RNA polymerase II were used to identify regulatory elements and genes that bind GR and are direct transcriptional targets. A panel of previously well-characterized corticotrope adenomas was used to correlate expression of CABLES1 with that of other markers. Results: GCs altered expression of 3 positive and 3 negative regulators of cell cycle progression. Two Myc genes (L-Myc and N-Myc) and E2F2 are repressed by GCs, whereas genes for the negative regulators of the cell cycle, Gadd45, Gadd45, and Cables1 are activated by GCs. Cables1 small interfering RNA knockdown strongly stimulates AtT-20 cell proliferation and antagonizes the growth inhibition produced by GCs. The Gadd45 and Cables1 genes have the hallmarks of direct GC targets. CABLES1 is expressed in normal human pituitary cells, but expression is lost in 55% of corticotrope adenomas, and this is strongly correlated with the loss of p27 Kip1 expression.
Conclusions: CABLES1 is a critical regulator of corticotrope proliferation that defines a pathway often inactivated in CD and links proliferation to GC resistance. (J Clin Endocrinol Metab

Document type :

Journal articles
Journal of Clinical Endocrinology and Metabolism, Endocrine Society, 2016, 101 (2), pp.513-522. <10.1210/jc.2015-3324>

Diagnosis and Treatment of Pituitary Adenomas

A Review
JAMA. 2017;317(5):516-524. doi:10.1001/jama.2016.19699

Importance  Pituitary adenomas may hypersecrete hormones or cause mass effects. Therefore, early diagnosis and treatment are important.

Observations  Prevalence of pituitary adenomas ranges from 1 in 865 adults to 1 in 2688 adults. Approximately 50% are microadenomas (<10 mm); the remainder are macroadenomas (≥10 mm).

Mass effects cause headache, hypopituitarism, and visual field defects. Treatments include transsphenoidal surgery, medical therapies, and radiotherapy. Prolactinomas account for 32% to 66% of adenomas and present with amenorrhea, loss of libido, galactorrhea, and infertility in women and loss of libido, erectile dysfunction, and infertility in men; they are generally treated with the dopamine agonists cabergoline and bromocriptine.

Growth hormone–secreting tumors account for 8% to 16% of tumors and usually present with enlargement of the lips, tongue, nose, hands, and feet and are diagnosed by elevated insulin-like growth factor 1 levels and growth hormone levels; initial treatment is surgical. Medical therapy with somatostatin analogues, cabergoline, and pegvisomant is often also needed.

Adrenocorticotropic hormone (ACTH)–secreting tumors account for 2% to 6% of adenomas and are associated with obesity, hypertension, diabetes, and other morbidity. Measurement of a late-night salivary cortisol level is the best screening test but petrosal sinus sampling for ACTH may be necessary to distinguish a pituitary from an ectopic source.

The primary treatment of Cushing disease (hypercortisolism due to ACTH-producing adenomas, which is the cause in approximately 65% of the cases of hypercortisolism) is adenoma resection and medical therapies including ketoconazole, mifepristone, and pasireotide.

Hyperthyroidism due to thyroid-stimulating hormone–secreting tumors accounts for 1% of tumors and is treated with surgery and somatostatin analogues if not surgically cured. Clinically nonfunctioning adenomas account for 15% to 54% of adenomas and present with mass effects; surgery is generally required, although incidentally found tumors can be followed if they are asymptomatic.

Conclusions and Relevance  Patients with pituitary adenomas should be identified at an early stage so that effective treatment can be implemented. For prolactinomas, initial therapy is generally dopamine agonists. For all other pituitary adenomas, initial therapy is generally transsphenoidal surgery with medical therapy being reserved for those not cured by surgery.

Read the full text here: http://jamanetwork.com/journals/jama/article-abstract/2600472

Metabolomic Biomarkers in Urine of Cushing’s Syndrome Patients

Int. J. Mol. Sci. 2017, 18(2), 294; doi:10.3390/ijms18020294 (registering DOI)
Department of Food Sciences, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland
Laboratory of Environmental Chemometrics, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
Department of Endocrinology and Internal Medicine, Medical University of Gdańsk, ul. Dębinki 7, 80-211 Gdańsk, Poland
Department ofEnvironmental Analytics, Institute for Environmental and Human Health Protection, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
Author to whom correspondence should be addressed.
Academic Editor: Ting-Li (Morgan) Han
Received: 5 December 2016 / Revised: 9 January 2017 / Accepted: 19 January 2017 / Published: 29 January 2017
(This article belongs to the Section Molecular Diagnostics)
Download PDF [1853 KB, uploaded 29 January 2017]

Abstract

Cushing’s syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS.

This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs).

Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing’s syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals.

The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects.

The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.

 

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

From http://www.mdpi.com/1422-0067/18/2/294

Bilateral testicular tumors resulting in recurrent Cushing’s syndrome after bilateral adrenalectomy

Corresponding author: Troy Puar, MRCP (UK), Department of Medicine, Div. of Endocrinology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands. Phone: +31 243614599, Fax: +31 243618809, e-mail: Troy_puar@cgh.com.sg
Received: July 14, 2016
Accepted: November 29, 2016
First Published Online: November 30, 2016

Recurrence of hypercortisolism in patients after bilateral adrenalectomy for Cushing’s disease is extremely rare.

We present a rare case of a 27-year-old man who previously underwent bilateral adrenalectomy for Cushing’s disease with complete clinical resolution. Cushingoid features recurred 12 years later, along with bilateral testicular enlargement. Hormonal tests confirmed ACTH-dependent Cushing’s. Surgical resection of the testicular tumors led to clinical and biochemical remission.

We report bilateral testicular tumors occurring in a patient with recurrent Cushing’s disease 12 years after bilateral adrenalectomy. Using mRNA expression analysis and steroid metabolome profiling, the tumors demonstrated both adrenocortical and gonadal steroidogenic properties, similar to testicular adrenal rest tumors found in patients with congenital adrenal hyperplasia. This suggests the presence of pluripotent cells even in patients without CAH.

– See more at: http://press.endocrine.org/doi/abs/10.1210/jc.2016-2702#sthash.F4lfWg9j.dpuf

Cushing’s Syndrome mutant PKAL205R exhibits altered substrate specificity

Joshua M Lubner, Kimberly L Dodge-Kafka, Cathrine R Carlson, George M Church, Michael F Chou, Daniel Schwartz
doi: https://doi.org/10.1101/091231
This article is a preprint and has not been peer-reviewed.

 

Abstract

The PKAL205R hotspot mutation has been implicated in Cushing’s Syndrome through hyperactive gain-of-function PKA signaling, however its influence on substrate specificity has not been investigated.

Here, we employ the Proteomic Peptide Library (ProPeL) approach to create high-resolution models for PKAWT and PKAL205R substrate specificity. We reveal that the L205R mutation reduces canonical hydrophobic preference at the substrate P+1 position, and increases acidic preference in downstream positions. Using these models, we designed peptide substrates that exhibit altered selectivity for specific PKA variants, and demonstrate the feasibility of selective PKAL205R loss-of-function signaling.

Through these results, we suggest that substrate rewiring may contribute to Cushing’s Syndrome disease etiology, and introduce a powerful new paradigm for investigating mutation-induced kinase substrate rewiring in human disease.

Full PDF at http://biorxiv.org/content/early/2016/12/05/091231.full.pdf+html

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