RAS-GTP levels are elevated in human NF1 peripheral nerve tumors

Guha, Abhishek; Lau, N.; Gutmann, David H.; Pawson, A.; Boss, Gerry R.

doi:10.1016/s0303-8467(97)81805-7

Cited by 73 publications

(90 citation statements)

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“…[2][3][4] Neurofibromin deficiency results in an increase in Ras-GTP and increased activation of its effectors. [2][3][4][5] These abnormalities contribute to cell transformation in NF1 patients. 3,4 Studies in Nf1-deficient mice, [6][7][8] and Drosophila flies 9 provide additional support for the significance of aberrant Ras-GTP in NF1.…”

mentioning

confidence: 99%

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

et al. 2006

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Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio-and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1 À/À , Nf1 þ /À , and Nf1 þ / þ MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD-independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.

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confidence: 99%

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

et al. 2006

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“…S1). 7 The RAD001/erlotinib -treated tumors did not show evident changes in tumor histology from those treated with RAD001 alone (data not shown).…”

Section: Rad001 Decreases Growth Of Established Mpnst Xenograftsmentioning

confidence: 88%

Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors

Johansson¹,

Mahller

Collins³

et al. 2008

Molecular Cancer Therapeutics

117

121

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Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with

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“…Both NF1-associated and sporadic MPNSTs show the loss or mutation of NF-1 gene expression [36] A large variety of human mutations has been identified such as total deletion of the gene, frame-shift mutation, in-frame deletion, missense mutation [37] and the risk of developing MPNST seems to depend on the type of mutation. Patients with small truncating NF-1 mutations have generally lower risk than patients with microdeletions including the entire NF-1 gene [38,39].…”

Section: Neurofibromas and Malignant Peripheral Nerve Sheath Tumoursmentioning

confidence: 99%

The Neurofibromatosis type 1:A dominantly inherited tumors-predisposing disorder

et al. 2009

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AbstractNeurofibromatosis type I (NF1) is a hereditary multisystem disease involving the skin and nervous system. It is the most common form of autosomal dominant phakomatoses with 100% penetrance but wide phenotypic variability. The NF1 gene is located on chromosome 17q11.2 and encodes for a tumour suppressor protein. Because affected individuals have an increased risk of tumor formation, this disorder is classified as inherited cancer syndrome. The risk of malignancies in NF1 affected patients is estimated to be 5–15% higher than in the general population. We reviewed clinical aspects and genetic mechanisms of tumorigenesis in NF1 affected patients.

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RAS-GTP levels are elevated in human NF1 peripheral nerve tumors

Cited by 73 publications

References 0 publications

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors

The Neurofibromatosis type 1:A dominantly inherited tumors-predisposing disorder

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