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 Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

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: 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...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

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

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>