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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/

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