Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Neurofibromin: It’s so degrading

06.02.2003


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:
http://www.cshl.org/

More articles from Health and Medicine:

nachricht Custom-tailored strategy against glioblastomas
26.09.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology

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: New welding process joins dissimilar sheets better

Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of light metals.
Scientists at the University of Stuttgart have now developed two new process variants that will considerably expand the areas of application for friction stir welding.
Technologie-Lizenz-Büro (TLB) GmbH supports the University of Stuttgart in patenting and marketing its innovations.

Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of...

Im Focus: First quantum photonic circuit with electrically driven light source

Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.

Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

HLF: From an experiment to an establishment

29.09.2016 | Event News

European Health Forum Gastein 2016 kicks off today

28.09.2016 | Event News

Laser use for neurosurgery and biofabrication - LaserForum 2016 focuses on medical technology

27.09.2016 | Event News

 
Latest News

New Multiferroic Materials from Building Blocks

29.09.2016 | Materials Sciences

Silicon Fluorescent Material Developed Enabling Observations under a Bright “Biological Optical Window”

29.09.2016 | Materials Sciences

X-shape Bio-inspired Structures

29.09.2016 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>