Disease relevance of Nf1

• In contrast, mitogenic activity present in normal human adult nerves and in neurofibromas from patients with type 1 neurofibromatosis analyzed in the absence of forskolin is largely inhibitable by anti-HGF [1].
• These data implicate Kit as one of the components leading to the Schwann cell hyperplasia observed in NF1 [2].
• Type 1 Neurofibromatosis (NF1) is characterized by the formation of neurofibromas, benign tumors composed mainly of Schwann cells, which can turn malignant to form neurofibrosarcomas [2].
• In this report, we show that platelet-derived growth factor (PDGF) BB, and to a lesser extent fibroblast growth factor 2, are mitogenic for two neurofibrosarcoma-derived Schwann cell lines, but not for a Schwann cell line derived from a schwannoma (from a non-NF1 patient) or for transformed rat Schwann cells [3].
• After nerve transection, no alteration in NF1 message level was detected, but neurofibromin levels increased, as assessed by immunohistochemistry and Western blotting, suggesting that, in vivo, neurofibromin expression in Schwann cells is post-transcriptionally induced during Wallerian degeneration [4].

High impact information on Nf1

• Thus, germline mutations in NF1 that cause neurofibromatosis 1 can also occur in somatic cells and contribute to the development of sporadic tumors, including tumors not associated with neurofibromatosis 1 [5].
• Here we present evidence that the ras proteins in malignant tumour cell lines from patients with type 1 neurofibromatosis are in a constitutively activated state, as judged by the guanine nucleotide bound to them, and are necessary for cellular proliferation [6].
• To better localize the end points of these translocation events, and the NF1 gene (NF1) itself, human cosmids were isolated and mapped in the immediate vicinity of NF1 [7].
• Balanced translocations, each involving chromosome 17q11.2, have been described in two patients with von Recklinghausen neurofibromatosis (NF1) [7].
• The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes [8].

Chemical compound and disease context of Nf1

• Neurofibromatosis type 2, a disease characterized by the formation of multiple nervous system tumors, especially schwannomas, is caused by mutation in the gene-encoding merlin/schwannomin [9].
• Recently described pheochromocytoma cell lines from neurofibromatosis knockout mice are shown to be novel models for signaling by the receptor tyrosine kinase ret, and purified enterochromaffin-like (ECL) cells are shown to offer new opportunities to study the shared and distinctive aspects of neuroendocrine function using a normal cell type [10].

Biological context of Nf1

• INTRODUCTION: Neurofibromatosis type 1 is caused by mutations in the NF1 gene encoding the Ras GTPase activating protein (Ras-GAP) neurofibromin [11].
• These symptoms are congenital, implying a role for neurofibromin in proper bone growth [11].
• Neurofibromin, the protein product of the Nf1 gene, is believed to act as a tumor suppressor, accelerating the conversion of the oncogene Ras to its inactive form [2].
• Thus a G(1) phase-specific protein, cyclin D1, accounts for two salient features of Schwann cell growth control: the promitotic response to cAMP and the antimitotic response to the Nf1 tumor suppressor [12].
• One cosmid probe, c11-1F10, demonstrated that both translocation breakpoints, and presumably NF1, are contained within a 600-kilobase Nru I fragment [7].

Anatomical context of Nf1

• We show, in addition, that at least one function of the Nf1 tumor suppressor is to antagonize the accumulation of cAMP and the expression of cyclin D1 in Schwann cells [12].
• To better map the location of the von Recklinghausen neurofibromatosis (NF1) gene, we have characterized a somatic cell hybrid designated 7AE-11 [13].
• Neurofibromin is enriched in the endoplasmic reticulum of CNS neurons [14].
• Neurofibromin is present in cell bodies and in axons, but is highly enriched in dendrites [14].
• Neurofibromin is highly enriched in large projection neurons, such as cortical and hippocampal pyramidal cells and cerebellar Purkinje cells [14].

Associations of Nf1 with chemical compounds

• Early lesion of N-nitroso-N-ethylurea-induced hamster neurofibromatosis model [15].
• We describe the abnormal expression of high levels of the Kit tyrosine kinase receptor in both NF1-derived Schwann cell lines and tissue, as compared to primary Schwann cells or schwannoma-derived cells [2].
• Failure to remove a significant proportion of the bound neurofibromin in the presence of EDTA and GDP implies that the binding of neurofibromin to p21c-Ha-ras-GMP-PNP results in the ras protein becoming resistant to guanine nucleotide exchange [16].
• Targets with demonstrated increases in both protein and mRNA abundances included neurofibromin, casein kinase IIbeta, the beta-subunit of the epithelial Na channel (beta-ENaC), 11beta-hydroxysteroid dehydrogenase type 2, and c-Fos [17].
• The product of the neurofibromatosis type II (NF2) tumor suppressor gene, merlin, is closely related to the ezrin-radixin-moesin (ERM) family, a group of proteins believed to link the cytoskeleton to the plasma membrane [18].

Regulatory relationships of Nf1

• These data suggest that rasGAP and neurofibromin are unable to downregulate Ras-GTP complexed to Raf-1 or B-raf [19].
• The rat neurofibromatosis type I (NF1) gene expresses several transcript isoforms which differ by the alternative splicing of exons 23a and 23b in the region encoding the GTPase-activating protein-related domain [20].
• A switch from the type 1 neurofibromin that can efficiently downregulate p21-ras to the type 2 isoform with reduced activity may facilitate a p21-ras signaling pathway associated with Schwann cell differentiation [21].

Other interactions of Nf1

• Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1 [12].
• Under conditions in which neurofibromin quantitatively binds to p21c-Ha-ras-GMP-PNP, we were unable to detect a complex between p21c-Ha-ras and GAP (GTPase-activating protein) [16].
• Competitive studies with the catalytic domain if neurofibromin, NF1-GRD, demonstrated that its interaction with Ras-GMPPNP is mutually exclusive with both Raf-1 and B-raf [19].
• Expression of Kit in neurofibromin-deficient human Schwann cells: role in Schwann cell hyperplasia associated with type 1 neurofibromatosis [2].
• Merlin, the neurofibromatosis type 2 gene product, and beta1 integrin associate in isolated and differentiating Schwann cells [9].

Analytical, diagnostic and therapeutic context of Nf1

• Neurofibromin was detected in the endothelial cell layer of rat cerebral vessels, renal arteries, and aorta by immunohistochemistry [22].
• Cultured bovine cerebral endothelial cells were found to express NF1 mRNA by RT-PCR and neurofibromin by Western immunoblotting and immunocytochemistry [22].
• To identify contexts in Schwann cells in which such mutations may play an important role, we measured the levels of NF1 mRNA and neurofibromin in rat sciatic nerve during development, after axotomy, and in cultured rat Schwann cells [4].
• In contrast to central nervous system neurons, neurons expressing the type 2 NF1 isoform were identified in the developing dorsal root ganglia and spinal cord by in situ hybridization using a type 2-specific oligonucleotide probe [23].
• Although NF1 mRNA levels peaked within 1-6 hr, the rise in neurofibromin was not apparent until 24-48 hr and peaked 72 hr after treatment [21].

References