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 Switch-in-a-cell electrifies life
18.12.2018 | Rice University

nachricht Plant biologists identify mechanism behind transition from insect to wind pollination
18.12.2018 | University of Toronto

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Data storage using individual molecules

Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.

Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Physicists found a correlation between the structure and magnetic properties of ceramics

18.12.2018 | Physics and Astronomy

Unique insights into an exotic matter state

18.12.2018 | Physics and Astronomy

Physicists studied the influence of magnetic field on thin film structures

18.12.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>