Proteasomal and Genetic Inactivation of the NF1 Tumor Suppressor in Gliomagenesis

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• 作者：Lauren T. McGillicuddy ; Jody A. Fromm ; Pablo E. Hollstein ; Sara Kubek ; Rameen Beroukhim ; Thomas De Raedt ; Bryan W. Johnson ; Sybil M.G. Williams ; Phioanh Nghiemphu ; Linda M. Liau ; Tim F. Cloughesy ; Paul S. Mischel ; Annabel Parret ; Jeanette Seiler ; Gerd Moldenhauer ; Klaus Scheffzek ; Anat O. Stemmer-Ra
• 刊名：Cancer Cell
• 出版年：2009
• 出版时间：7 July 2009
• 年：2009
• 卷：16
• 期：1
• 页码：44-54
• 全文大小：896 K

文摘

Summary

Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity.