Neurofibromatosis type 1 gene mutations in neuroblastoma

Murthy, Anita E.; Hannigan, Gregory E.; Jacoby, Lee B.; Menon, Anil G.; Gusella, James F.; Bernards, André

doi:10.1038/ng0193-62

Cited by 140 publications

(54 citation statements)

References 28 publications

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“…An analogous observation with the two main mammalian p21-ras-GAPs, p120-GAP and neuro®bromin (neuro®bromatosis 1 gene product), has been made. In these studies, neuro®bromin expression was reduced or absent in several di erent tumor types, but no changes in p120-GAP expression were observed (Johnson et al, 1993;The et al, 1993).…”

mentioning

confidence: 70%

Alterations in the rap1 signaling pathway are common in human gliomas

et al. 1997

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Several inherited predisposition to cancer syndromes are associated with the development of nervous system tumors. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which a ected individuals are at risk for developing astrocytomas. One of the genes responsible for this disorder is TSC2, located on chromosome 16p, and encoding a 180 kDa protein (tuberin) that functions in part as a negative regulator of rap1. Previous studies from our laboratory demonstrated that 30% of sporadic astrocytomas have reduced or absent tuberin expression. In addition to loss of tuberin in sporadic astrocytomas, aberrant rap1 mediated signaling may also result from overexpression of rap1. In this study, we test the hypothesis that alterations in the rap1 signaling pathway are frequently observed in certain subsets of gliomas compared to other tumors of the nervous system. Analysis of sporadic astrocytomas and ependymomas demonstrated either increased rap1 or reduced/absent tuberin protein expression in 50 ± 60% of di erent cohorts of these gliomas, compared to 30 ± 33% of sporadic schwannomas and meningiomas and none of eight oligodendrocyte tumors. These results suggest that alterations in the rap1 signaling pathway are important in the development of certain sporadic human gliomas.

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mentioning

confidence: 70%

Alterations in the rap1 signaling pathway are common in human gliomas

et al. 1997

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“…Earlier studies on other malignancies have reported mutations of the NF1 gene leading to loss of gene expression. [7][8][9] The shortening of the cell cycle in poorly differentiated cancer cells could lead to diminution of primary transcripts from large genes such as NF1. However, this does not seem to be the case, eg, in RB gene expression in TCC, which is a large gene.…”

Section: Discussionmentioning

confidence: 99%

Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

Aaltonen

Boström

Söderström

et al. 1999

The American Journal of Pathology

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The NF1 gene product (neurofibromin) is known to act as a tumor suppressor protein by inactivating ras. The best documented factors involved in urinary bladder transitional cell carcinoma (TCC) are ras proto-oncogene activation and p53 suppressor gene mutations. This is the first study reporting alterations in NF1 gene expression in TCC. We examined NF1 gene expression in a total of 29 surgical urinary bladder TCC specimens representing grades 1 to 3 and in three cell lines , RT4 , 5637 , and T24 (representing grades 1 to 3 , respectively). Decreased NF1 gene expression was observed in 23 of 29 (83%) TCC specimens as estimated by immunohistochemistry , the decrease being more pronounced in high-grade tumors. NF1 mRNA levels were markedly lower in TCC tissue compared with adjacent non-neoplastic urothelium, as studied by in situ hybridization for grade 3 TCC.

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“…Three neuroblastoma cell lines (90-4, 90-6, 90-10SK-n-SH) were also used for our methylation studies (kindly provided by Dr Andre Bernards; The et al, 1993). Brie¯y, total RNA from several human neuroblastoma cell lines was assessed by blot analysis using a 5' NF1 cDNA probe, representing nucleotides 1748 to 2673 (Genbank accession number M89914).…”

Section: Methylation In the Human Nf1 Promoter Regionmentioning

confidence: 99%

Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors

et al. 1999

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Tumour suppressor genes and growth regulatory genes are frequent targets for methylation defects that can result in aberrant expression and mutagenesis. We have established a methylation map of the promoter region of the neuro®bromatosis (NF1) gene and demonstrated functional sensitivity for methylation at speci®c sites for the SP1 and CRE binding (CREB) proteins in the NF1 regulatory region. We evaluated the methylation status of CpG dinucleotides within ®ve promoter subregions in the human and mouse homologues of the neuro®bromatosis (NF1) genes. Three 5' subregions were found to be consistently methylated in all the tissues analysed. In contrast, DNA methylation was absent in the vicinity of the transcription start site bounded by SP1 recognition sequences. Gelshift assays showed that methylation speci®cally inhibits the CREB transcription factor from binding to its recognition site at the NF1 transcription start site. Furthermore, SP1 elements within the NF1 promoter are methylation sensitive, particularly when methylation is present on the antisense strand. We propose that for NF1 as with several other tumour suppressor genes, CpG methylation occurs in a complex, site-speci®c manner with the maintenance of a methylation-free promoter region bounded by SP1 binding sites that allow an accessible promoter to be retained. When these SP1 boundaries are breached, methylation can sweep in, rendering the promoter inaccessible for speci®c methylation-sensitive transcription factors and leading to a loss of functional integrity of the methylation-free CpG island.

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Neurofibromatosis type 1 gene mutations in neuroblastoma

Cited by 140 publications

References 28 publications

Alterations in the rap1 signaling pathway are common in human gliomas

Alterations in the rap1 signaling pathway are common in human gliomas

Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors

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