Increased noise as an effect of haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 in vitro

The NF1 gene, which is altered in patients with type 1 neurofibromatosis, has been postulated to function as a tumor suppressor gene. The NF1 protein product neurofibromin stimulates the intrinsic GTPase activity of active GTP-bound Ras, thereby inactivating it. Consistent with a tumor suppressor function, we have found that the introduction of NF1 in melanoma cell lines that are deficient in neurofibromin inhibited their growth and induced their differentiation. In addition, overexpression of neurofibromin in NIH 3T3 cells was growth inhibitory but did not alter the level of GTP.Ras in the cells. Transformation by v-ras, whose protein product is resistant to GTPase stimulation by neurofibromin, was inhibited in a cell line overexpressing neurofibromin, while transformation by v-raf was not altered. The results demonstrate that NF1 is a tumor suppressor gene that can inhibit Ras-dependent growth by a regulatory mechanism that is independent of neurofibromin's ability to stimulate Ras GTPase.

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Molecular genetic investigation of the neurofibromatosis type 2 tumor suppressor gene in sporadic meningioma

Journal of Neurosurgery ◽

10.3171/jns.1996.84.5.0847 ◽

1996 ◽

Vol 84 (5) ◽

pp. 847-851 ◽

Cited By ~ 58

Author(s):

Takehiko Harada ◽

Richard M. Irving ◽

John H. Xuereb ◽

David E. Barton ◽

David G. Hardy ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Molecular Genetic ◽

Gene Mutations ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Neurofibromatosis Type 2 ◽

Chromosome 22 ◽

Sporadic Meningioma

✓ The authors investigated the role of somatic mutations of the neurofibromatosis type 2 (NF2) gene in sporadic meningioma. Neurofibromatosis 2 is a dominantly inherited familial tumor syndrome predisposing affected patients to a variety of central nervous system tumors including vestibular schwannoma and meningioma. Neurofibromatosis type 2 is caused by germline mutations in the NF2 tumor suppressor gene. In addition, the authors and others have reported that somatic NF2 gene mutations occur frequently in nonfamilial vestibular schwannoma. In this study, molecular genetic analysis was performed on 23 nonfamilial meningiomas. Paired DNA samples extracted from the blood and tumors of the patients were analyzed for loss of heterozygosity (LOH) in the region of the NF2 gene on chromosome 22 using closely linked DNA markers. The NF2 gene mutations were sought by single-stranded conformation polymorphism analysis and DNA sequencing. Fourteen (61%) of 23 meningiomas showed LOH in the region of the NF2 gene on chromosome 22. Somatic NF2 gene mutations were detected in eight meningiomas (35%) after screening all 17 exons. All tumors with NF2 gene mutations showed simultaneous chromosome 22 LOH. Review of the histopathological findings of the cases studied did not demonstrate any predominance of genetic abnormalities in a particular histological type of meningioma. These results are compatible with the hypothesis that the NF2 gene acts as a tumor suppressor and that its inactivation is important in the pathogenesis of sporadic meningioma.

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Mutations of the NF1 Gene in Children With Juvenile Myelomonocytic Leukemia Without Clinical Evidence of Neurofibromatosis, Type 1

Blood ◽

10.1182/blood.v92.1.267.413a31_267_272 ◽

1998 ◽

Vol 92 (1) ◽

pp. 267-272 ◽

Cited By ~ 138

Author(s):

Lucy E. Side ◽

Peter D. Emanuel ◽

Brigit Taylor ◽

Janet Franklin ◽

Patricia Thompson ◽

...

Keyword(s):

Clinical Diagnosis ◽

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Juvenile Myelomonocytic Leukemia ◽

Translation System ◽

Polymorphism Analysis ◽

Single Stranded Conformational Polymorphism ◽

Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on Ras proteins. The purpose of this study was to determine if the NF1gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1mutations that resulted in a truncated protein. Single-stranded conformational polymorphism analysis was used to detect RASpoint mutations in these samples. We confirmed mutations of NF1in three leukemias, one of which also showed loss of the normalNF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested and this suggests that JMML may be the presenting feature of NF1 in some children. Activating RASmutations were found in four patients; as expected, none of these samples harbored NF1 mutations. Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases.

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