NEW YORK (Reuters Health) - A new study suggests that only one of the three main isoforms of RAS protein, K-RAS, is involved in the tumor growth that occurs in neurofibromatosis 1 (NF1).
These findings explain why existing NF1 treatments, which target N-RAS and H-RAS but do not affect K-RAS, are often ineffective, Dr. David H. Gutmann of Washington University School of Medicine in St. Louis and colleagues report.
Patients with NF1, who carry a single mutated form of the NF1 gene, develop both benign and malignant nervous system tumors in childhood and adolescence. The NF1 gene product neurofibromin normally plays a key role in converting the active form of RAS, RAS-GTP, into the non-active RAS-GDP conformation.
Loss of neurofibromin therefore results in excess RAS activation that in turn leads to cell proliferation and decreased apoptosis, the investigators explain in the January 1st issue of Cancer Research.
But clinical trials of farnesyltransferase inhibitors to block RAS activity have had disappointing results.
Evidence is growing that the three RAS isoforms have different physiological effects, Dr. Gutmann and colleagues note in their report, so they conducted the current study to identify the effect of blocking NF1 in astrocytes on H-RAS, K-RAS and N-RAS.
The researchers first assessed RAS activity in astrocytes after inactivating neurofibromin. Only K-RAS was hyperactivated, the researchers found. They also found activating K-RAS produced effects similar to those of neurofibromin loss, while activation of H-RAS did not.
K-RAS activation also exerted effects similar to NF1 inactivation in mice. Previous research by the team had shown that mice heterozygous for NF1 with astrocyte Nf1 inactivation developed optic pathway gliomas. In the current study the researchers showed that animals heterozygous for NF1 with hyperactivated K-RAS developed similar tumors.
“Collectively, our results demonstrate that K-RAS is the primary target for neurofibromin GAP activity in vitro and in vivo, and that K-RAS activation in astrocytes recapitulates the biochemical, biological and tumorigenic properties of neurofibromin loss,” the researchers conclude. The findings also point the way toward developing potentially more effective therapies.
Source: Cancer Res 2005. [ Google search on this article ]
MeSH Headings:Animal Diseases: Disease Models, Animal: Proto-Oncogene Proteins: Genes, ras: Proto-Oncogene Protein p21(ras): Genes, Neurofibromatosis 1: ras Proteins: Monomeric GTP-Binding Proteins: etiology: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
