Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Genetic defect triggers endless recycling

15.12.2014

Benign tumors in the pituitary gland are responsible when adrenal gland cells secrete the stress hormone cortisol unchecked. An international team of scientists has now succeeded in mapping out in detail the molecular processes that lie behind this.

Patients suffering from Cushing’s syndrome are often easy to recognize: they put on considerable weight around the midriff, their faces become rounder, and their necks sturdier. In addition to these external symptoms, most sufferers also have higher blood pressure, develop muscle weakness, become diabetic, and are extremely prone to infections. In many cases, surgery is a successful treatment for Cushing’s syndrome; if it is left untreated, patients die from infections or cardiovascular problems.

Now scientists from Würzburg, Munich, and Tokyo have managed to make some progress in the search for the triggers of this disease. They have discovered at molecular level the mechanisms that are responsible for causing benign tumors of the pituitary gland to trigger Cushing’s syndrome. A leading role in this was played by the following professors: Martin Fassnacht (Würzburg University Hospital), Martin Reincke (LMU Munich University Hospital), and Masayuki Komada (Yokohama, Japan). They present their work in the current issue of the journal Nature Genetics.

Never-ending hormone secretion

A hormone is the trigger for all the symptoms of Cushing’s syndrome: cortisol – also known colloquially as cortisone. This stress hormone has important roles to play in metabolism; it is only when it is secreted in an uncontrolled manner that it throws the organism into chaos. Cortisol secretion in the adrenal gland is controlled by another hormone – adrenocorticotropin (ACTH), which is produced in the pituitary gland. If a benign tumor forms there, the gland produces ACTH unchecked, thereby raising the level of cortisol. How exactly this happens has been unclear until now.

“We have now been able to show, for the first time, that in the tumor cells of more than a third of patients there is as specific genetic mutation to an enzyme known as ubiquitin-specific protease 8,” explains Martin Fassnacht. This discovery was founded on a precise genetic characterization of benign pituitary gland tumors that produce ACTH, adds Fassnacht’s colleague and one of the lead authors of the publication, Dr. Silviu Sbiera.

Genetic defect leads to a fatal chain reaction

Ubiquitin-specific protease 8, or USP8 for short, assumes a key role when it comes to recycling proteins that are no longer needed inside cells. This also applies to the epidermal growth factor receptor: this is degraded and disposed of in the cell whenever the USP8 gene is not active. As the scientists revealed, the now discovered genetic mutations cause USP8 to remain durably activated. As a result, proteins of the epidermal growth factor receptor that are permanently no longer needed are recycled instead of disposed of as they actually should be. “In a life-threatening chain reaction, first ACTH and then cortisol are produced without restraint,” explains Fassnacht. The USP8 mutations represent a significant discovery. “They open up entirely new diagnostic and therapeutic avenues for treating Cushing’s syndrome,” adds Martin Reincke from the LMU.

The research project brought together the hormone researchers of the University of Würzburg with teams from the LMU Munich, the Helmholtz Center Munich, the Max Planck Institute of Psychiatry in Munich, and the Tokyo Institute of Technology, Yokohama (Japan). The work received support from various parties including the Federal Ministry of Education and Research, within the framework of the E-Rare program, and the University of Würzburg’s Interdisciplinary Center for Clinical Research.

Sights set on Cushing’s syndrome

In the search for the causes of Cushing’s syndrome, Würzburg endocrinologists led by Professor Martin Fassnacht and Professor Bruno Allolio, in collaboration with Dr. Davide Calebiro and Professor Martin Lohse from the Rudolf Virchow Center, have already achieved multiple successes this year. For example, they have been able to point to mutations in a gene of the adrenal gland as a frequent cause of the secretion of abnormally high levels of cortisol. They reported on the findings of this work in the New England Journal of Medicine in February. And just a few days ago they were able to publish further discoveries in the journal Nature Communications: the Würzburg researchers, under the leadership of pharmacologist Dr. Davide Calebiro, further mapped out the exact mechanisms of the mutation in the adrenal gland.

“Mutations in the deubiquitinase gene USP8 cause Cushing’s disease” Martin Reincke, Silviu Sbiera, Akira Hayakawa, Marily Theodoropoulou, Andrea Osswald, Felix Beuschlein, Thomas Meitinger, Emi Mizuno-Yamasaki, Kohei Kawaguchi, Yasushi Saeki, Keiji Tanaka, Thomas Wieland, Elisabeth Graf, Wolfgang Saeger, Cristina L Ronchi, Bruno Allolio, Michael Buchfelder, Tim M Strom, Martin Fassnacht & Masayuki Komada. Nature Genetics, doi:10.1038/ng.3166

Contact

Professor Martin Fassnacht, Department of Medicine I, Würzburg University Hospital,
T: +49 (0)931 201-39021, e-mail: fassnacht_m@ukw.de

Gunnar Bartsch | idw - Informationsdienst Wissenschaft
Further information:
http://www.uni-wuerzburg.de

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>