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[Cancer Research 65, 236-245, January 1, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

Glioma Formation in Neurofibromatosis 1 Reflects Preferential Activation of K-RAS in Astrocytes

Biplab Dasgupta1, Wen Li1, Arie Perry2 and David H. Gutmann1

Departments of 1 Neurology and 2 Pathology (Neuropathology), Washington University School of Medicine, St. Louis, Missouri

Request for reprint: David H. Gutmann, Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-362-7379; Fax: 314-362-2388. E-mail: gutmannd{at}neuro.wustl.edu.

Children with the tumor predisposition syndrome, neurofibromatosis 1 (NF1), develop optic pathway gliomas. The NF1 gene product, neurofibromin, functions as a negative regulator of RAS, such that NF1 inactivation results in RAS hyperactivation. Recent studies have highlighted the divergent biological and biochemical properties of the various RAS isoforms, which prompted us to examine the consequence of Nf1 inactivation in astrocytes on RAS isoform activation in vitro and in vivo. In this report, we show that only K-RAS is activated in Nf1–/– astrocytes and that activation of K-RAS, but not H-RAS, accounts for the proliferative advantage and abnormal actin cytoskeleton–mediated processes observed in Nf1–/– astrocytes in vitro. Moreover, dominant inhibitory K-RAS corrects these abnormalities in Nf1–/– astrocytes invitro. Lastly, we show that Nf1+/– mice with astrocyte-specific activated K-RAS expression in vivo develop optic pathway gliomas, similar to our previously reported Nf1+/– mice with astrocyte Nf1 inactivation. Collectively, our results show that K-RAS is the primary target for neurofibromin GTPase-activating protein activity in vitro and in vivo and that K-RAS activation in astrocytes recapitulates the biochemical, biological, and tumorigenic properties of neurofibromin loss.

Key Words: Optic pathway gliomas • NF1, neurofibromatosis • GTPase-activating protein • farnesyltransferase inhibitor; geranylgeranyltransferase inhibitor • K-RAS • 00-00-02 Brain/central nervous system cancers • 02-05-01 Mechanisms and signaling events




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