Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Neurofibromin: It’s so degrading


Dr. Tyler Jacks of MIT and the Howard Hughes Medical Institute, Karen Cichowski of Brigham and Women’s Hospital and Harvard Medical School, and their colleagues have discovered how neurofibromin, a key regulator of the ras oncogene, is, itself, regulated. This discovery has promising therapeutic implications for the treatment of neurofibromatosis type I (NF1), a common hereditary disease that results from mutations in the neurofibromin gene, as well as the ~30% of human tumors that have altered Ras activity.

The report is published in the February 15th issue of Genes & Development.

Neurofibromin is a tumor suppressor protein encoded by the Nf1 gene on human chromosome 17. Neurofibromin helps protect cells against cancer by suppressing Ras, a potent activator of cell growth and proliferation. People with mutations in the Nf1 gene develop neurofibromatosis type I (NF1), a neurological disorder that affects 1 in 3,500 people world-wide. NF1 patients develop benign tumors along their peripheral and optic nerves, as well as café-au-lait skin spots. NF1 is also associated with an increased risk of malignant neurological tumor development and childhood learning disabilities.

Although the Nf1 gene was identified in 1990, this work by Drs. Jacks, Cichowski and colleagues is the first report of how neurofibromin activity is regulated inside the cell.

"NF1 is a quite common and often quite devastating genetic disease, and yet we know rather little about the protein whose loss underlies it. This work begins to define the details of the normal regulation of the neurofibromin protein, and we hope that this new information will help guide the development of agents that will be useful in NF1 treatment and prevention," explains Dr. Jacks.

Under normal, growth-conducive conditions, small, secreted molecules called growth factors bind to receptors on the cell surface to trigger cellular proliferation. Drs. Jacks, Cichowski and colleagues found that this growth factor-mediated activation of cell division entails the destruction of neurofibromin protein by the so-called "ubiquitin-proteasome pathway" – a specialized intracellular protein-degradation cascade -- and the subsequent activation of Ras. However, the researchers also found that shortly after neurofibromin is degraded, its levels re-elevate to attenuate Ras activity and prevent excessive cell proliferation.

Since Nf1-deficient mice die during embryogenesis, Drs. Jacks, Cichowski and colleagues genetically engineered embryonic mouse cells to lack either one or both copies of the Nf1 gene, generating Nf1 heterozygous, or Nf1 homozygous cells, respectively. Nf1 homozygous cells were hypersensitive to growth factors: Due to their enhanced activation of Ras, Nf1 homozygous cells proliferated in response to low (sub-threshold) levels of growth factors, and continued dividing for extended periods of time. The elevated expression of Ras in Nf1 homozygous cells is thought to contribute to tumor formation NF1 patients.

The researchers also observed that Nf1 heterozygous cells show an increased sensitivity to growth factors, although not as marked as that of the Nf1 homozygous cells. This observation suggests that even diminished neurofibromin levels (resulting from the loss of one copy of the Nf1 gene) can adversely affect normal cell behavior, and may underlie the more subtle clinical features of NF1, like learning disabilities.

Ultimately, the elucidation of this neurofibromin regulatory network will aid in the development of targeted therapies to block neurofibromin degradation in NF1 patients, and perhaps also in some subset of the cancers in which amplified Ras activity confers upon cells the tumorigenic capacity for unregulated growth and proliferation.

Michele McDonough | EurekAlert!
Further information:

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Space observation with radar to secure Germany's space infrastructure

Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.

The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...

Im Focus: Researchers Discover New Anti-Cancer Protein

An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.

The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...

Im Focus: Researchers at Fraunhofer monitor re-entry of Chinese space station Tiangong-1

In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.

Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...

Im Focus: Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.

They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

New solar solutions for sustainable buildings and cities

23.03.2018 | Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

Latest News

For graphite pellets, just add elbow grease

23.03.2018 | Materials Sciences

Unique communication strategy discovered in stem cell pathway controlling plant growth

23.03.2018 | Agricultural and Forestry Science

Sharpening the X-ray view of the nanocosm

23.03.2018 | Physics and Astronomy

Science & Research
Overview of more VideoLinks >>>