The NF1 gene encodes neurofibromin, a cytoplasmic protein that is predominantly expressed in neurons, Schwann cells, oligodendrocytes, and leukocytes. It is a multidomain molecule with the capacity to regulate several intracellular processes, including the RAS (see 190020)-cyclic AMP pathway, the ERK (600997)/MAP (see 600178) kinase cascade, adenylyl cyclase, and cytoskeletal assembly (summary by Trovo-Marqui and Tajara, 2006).
神経細胞、シュワン細胞、オリゴデンドロサイト、白血球に主に発現している。RAS、cAMP などの経路に関与する。
Gene Function
DeClue et al. (1992) presented evidence implicating the NF1 protein as a tumor suppressor gene product that negatively regulates p21(ras) (see 190020) and defined a 'positive' growth role for RAS activity in NF1 malignancies.（radを抑制的にコントロールするがん抑制遺伝子）
Basu et al. (1992) presented evidence supporting the hypothesis that NF1 is a tumor-suppressor gene whose product acts upstream of the RAS proteins. They showed that the RAS proteins in malignant tumor cell lines from patients with NF1 were in a constitutively activated state as measured by the ratio of the guanine nucleotides bound to them, i.e., the ratio of GTP (active) to GDP (inactive). Transforming mutants of p21(ras) bind large amounts of GTP, whereas wildtype p21(ras) is almost entirely GDP-bound.（radの上流に働くがん抑制遺伝子。）
Nakafuku et al. (1993) took advantage of the yeast RAS system to isolate mutants in the RAS GTPase activating protein-related domain of the NF1 gene product (NF1-GRD) that can act as antioncogenes specific for oncogenic RAS. They demonstrated that these mutant NF1-GRDs, when expressed in mammalian cells, were able to induce morphologic reversion of RAS-transformed NIH 3T3 cells.（）
Johnson et al. (1993) stated that in schwannoma cell lines from patients with neurofibromatosis, loss of neurofibromin is associated with impaired regulation of GTP/RAS. They analyzed other neural crest-derived tumor cell lines and showed that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neurofibromatosis also contained reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NF1 locus. In contrast to the schwannoma cell lines, however, GTP/RAS was appropriately regulated in the melanoma and neuroblastoma lines that were deficient in neurofibromin, even when HRAS (190020) was overexpressed. These results demonstrated that some neural crest tumors not associated with neurofibromatosis have acquired somatically inactivated NF1 genes and suggested a tumor-suppressor function for neurofibromin that is independent of RAS GTPase activation.
Silva et al. (1997) cited several studies that suggested a role of neurofibromin in brain function. The expression of the NF1 gene is largely restricted to neuronal tissues in the adult. This GTPase-activating protein may act as a negative regulator of neurotrophin (see BDNF; 113505)-mediated signaling. They also noted immunohistochemical studies that suggested that activation of astrocytes may be common in the brain of NF1 patients.
In a review of the molecular neurobiology of human cognition, Weeber and Sweatt (2002) presented an overview of the RAS-ERK-CREB pathway, including the function of NF1. The authors discussed publications that implicated dysfunction of this signal transduction cascade in cognitive defects, including mental retardation caused by mutation in the NF1 gene.
Vogel et al. (1995) used a targeted disruption of the NF1 gene in mice to examine the role of neurofibromin in the acquisition of neurotrophin dependence in embryonic neurons. They showed that both neural crest- and placode-derived sensory neurons isolated from NF1 -/- embryos develop, extend neurites, and survive in the absence of neurotrophins, whereas their wildtype counterparts die rapidly unless nerve growth factor (162030) or BDNF is added to the culture medium. Moreover, NF1 -/- sympathetic neurons survive for extended periods and acquire mature morphology in the presence of NGF-blocking antibodies. These results were considered by Vogel et al. (1995) as consistent with a model wherein neurofibromin acts as a negative regulator of neurotrophin-mediated signaling for survival of embryonic peripheral neurons.
For the most part the NF1 tumor suppressor acts through the interaction of its GRD with the product of the RAS protooncogene. Skuse et al. (1996) discovered an mRNA editing site within the NF1 mRNA. Editing at this site changes a cytidine at nucleotide 2914 to a uridine, creating an in-frame translation stop codon. The edited transcript, if translated, would produce a protein truncated in the N-terminal region of the GRD, thereby inactivating the NF1 tumor-suppressor function. Analysis of RNA from a variety of cell lines, tumors, and peripheral blood cells revealed that the NF1 mRNA undergoes editing, to different extents, in every cell type studied. Three tumors analyzed as part of their study, an astrocytoma, a neurofibroma, and a neurofibrosarcoma, each had levels of NF1 mRNA editing substantially higher than did peripheral blood leukocytes. To investigate the role played by editing in NF1 tumorigenesis, Cappione et al. (1997) analyzed RNA from 19 NF1 and 4 non-NF1 tumors. (The authors referred to the editing site as nucleotide 3916.) They observed varying levels in NF1 mRNA editing in different tumors, with a higher range of editing in more malignant tumors (e.g., neurofibrosarcomas) compared to benign tumors (cutaneous neurofibromas). Plexiform neurofibromas had an intermediate range of levels of NF1 mRNA editing. The constitutional levels of NF1 mRNA editing varied slightly in NF1 individuals but were consistent with the levels observed in non-NF1 individuals. In every case, there was a greater level of NF1 mRNA editing in the tumor than in the nontumor tissue from the same patient. These results suggested to Cappione et al. (1997) that inappropriately high levels of NF1 mRNA editing indeed plays a role in NF1 tumorigenesis and that editing may result in the functional equivalent of biallelic inactivation of the NF1 tumor suppressor.
Mukhopadhyay et al. (2002) studied C-to-U RNA editing in peripheral nerve sheath tumor samples (PNSTs) from 34 patients with NF1. Whereas most showed low levels of RNA editing, 8 of the 34 tumors demonstrated 3 to 12% C-to-U editing of NF1 RNA. These tumors demonstrated 2 distinguishing characteristics. First, these PNSTs expressed APOBEC1 (600130) mRNA, the catalytic deaminase of the holoenzyme that edits APOB (107730) RNA. Second, NF1 RNA from these PNSTs contained increased proportions of an alternatively spliced exon, 23A, downstream of the edited base in which editing occurs preferentially. These findings, together with results of both in vivo and in vitro experiments with APOBEC1, strongly suggested an important mechanistic linkage between NF1 RNA splicing and C-to-U editing and provided a basis for understanding the heterogeneity of posttranscriptional regulation of NF1 expression.
The NF1 tumor suppressor protein is thought to restrict cell proliferation by functioning as a Ras-specific guanosine triphosphatase-activating protein. However, The et al. (1997) found that Drosophila homozygous for null mutations of an NF1 homolog show no obvious signs of perturbed RAS1-mediated signaling. Loss of NF1 resulted in a reduction in size of larvae, pupae, and adults. This size defect was not modified by manipulating RAS1 signaling but was restored by expression of activated adenosine 3-prime, 5-prime-monophosphate -dependent protein kinase (PKA; see 176911). Thus, NF1 and PKA appear to interact in a pathway that controls the overall growth of Drosophila. Guo et al. (1997) showed, from a study of Drosophila NF1 mutants, that NF1 is essential for the cellular response to the neuropeptide PACAP38 (pituitary adenylyl cyclase-adenosine activating polypeptide) at the neuromuscular junction. The peptide induced a 3-prime, 5-prime-monophosphate (cAMP) pathway. This response was eliminated in NF1 mutants. NF1 appeared to regulate the rutabaga-encoded adenylyl cyclase rather than the RAS-RAF pathway. Moreover, the NF1 defect was rescued by the exposure of cells to pharmacologic treatment that increased concentrations of cAMP.
Ras特異的なGTP加水分解酵素活性化タンパク質として作用することで、がん抑制遺伝子の機能を持つ。
Gutmann (2001) reviewed the functions of neurofibromin and merlin, the product of the NF2 gene (607379), in tumor suppression and cell-cell signaling, respectively.
Trovo-Marqui and Tajara (2006) provided a detailed review of neurofibromin and its role in neurofibromatosis.
Neurofibromin
Alternative name(s):
Neurofibromatosis-related protein NF-1
Cleaved into the following chain:
Neurofibromin truncated
Gene names
Name: NF1
Function
Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity. Ref.16 Ref.18
Tissue specificity
Detected in brain, peripheral nerve, lung, colon and muscle. Ref.16
Domain
Binds phospholipids via its C-terminal CRAL-TRIO domain. Binds primarily glycerophospholipids with monounsaturated C18:1 and/or C16:1 fatty acid moieties and a phosphatidylethanolamine or phosphatidylcholine headgroup. Has lesser affinity for lipids containing phosphatidylserine and phosphatidylinositol. Ref.33 Ref.34 Ref.35
Involvement in disease
Neurofibromatosis 1 (NF1) [MIM:162200]: A disease characterized by patches of skin pigmentation (cafe-au-lait spots), Lisch nodules of the iris, tumors in the peripheral nervous system and fibromatous skin tumors. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10 Ref.35 Ref.37 Ref.40 Ref.41 Ref.42 Ref.43 Ref.44 Ref.45 Ref.46 Ref.47 Ref.48 Ref.49 Ref.50 Ref.51 Ref.52 Ref.53 Ref.54 Ref.56 Ref.58 Ref.59 Ref.61 Ref.62 Ref.63 Ref.64 Ref.65 Ref.66 Ref.67 Ref.68 Ref.73
Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages.
Note: The disease is caused by mutations affecting the gene represented in this entry.
Watson syndrome (WS) [MIM:193520]: A syndrome characterized by the presence of pulmonary stenosis, cafe-au-lait spots, and mental retardation. It is considered as an atypical form of neurofibromatosis.
Note: The disease is caused by mutations affecting the gene represented in this entry.
Familial spinal neurofibromatosis (FSNF) [MIM:162210]: Considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.57
神経線維腫症
白血病
若年性骨髄単球性白血病
ヌーナン症候群（顔面の奇形、低身長、眼間隔離、新規系、難聴、出欠素因など）
大腸がん
Neurofibromatosis-Noonan syndrome (NFNS) [MIM:601321]: Characterized by manifestations of both NF1 and Noonan syndrome (NS). NS is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.60 Ref.69 Ref.71
Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
Note: The gene represented in this entry may be involved in disease pathogenesis.
Sequence similarities
Contains 1 CRAL-TRIO domain.
Contains 1 Ras-GAP domain.
Caution
Was originally (Ref.44) thought to be associated with LEOPARD (LS), an autosomal dominant syndrome.
RNA editing
Edited at position 1306.
The stop codon (UGA) at position 1306 is created by RNA editing. Various levels of RNA editing occurs in peripheral nerve-sheath tumor samples (PNSTs) from patients with NF1. Preferentially observed in transcripts containing exon 23A. Ref.19 Ref.20
