Linkage studies with chromosome 17 DNA markers in 45 neurofibromatosis 1 families

Stephens, Karen; Riccardi, Vincent M.; Rising, Marcia; Ng, Siu Kin; Collins, Francis S.; Rediker, Kenneth; Powers, Jody A.; Parker, Carol E.; Donis-Keller, Helen

doi:10.1016/0888-7543(87)90037-1

Cited by 25 publications

(14 citation statements)

References 8 publications

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“…1 is an autosomal dominantly inherited disorder with an estimated prevalence of 1 in 3000 people (1). The hallmarks of NF1 include development of benign tumors of the peripheral nervous system and increased risk of malignancies.…”

Section: Neurofibromatosis Type 1 (Nf1)mentioning

confidence: 99%

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Hirayama

Kobayashi

Mizuguchi

et al. 2013

Molecular & Cellular Proteomics

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Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up-or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, "dynein IC2-GR-COX-1 signaling," was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural abnormalities are, in part, caused by upregulation of dynein IC2-GR-COX-1 signaling, which may be a novel therapeutic target for NF1. Neurofibromatosis type 1 (NF1)1 is an autosomal dominantly inherited disorder with an estimated prevalence of 1 in 3000 people (1). The hallmarks of NF1 include development of benign tumors of the peripheral nervous system and increased risk of malignancies. The phenotype of NF1 is highly variable, with several organ systems affected including the skin, bones, irises, and central and peripheral nervous systems. The effects on the nervous system are manifested in multiple neurofibroma, gliomas, and learning disabilities.The NF1 gene is located on chromosome 17q11.2 and encodes a large protein of 2818 amino acids, neurofibromin (2). Because the great majority of NF1 gene mutations frequently found in NF1 patients disturb the expression of intact neurofibromin, functional disruption of neurofibromin is potentially relevant to the expression of some or all of the abnormalities that occur in NF1 patients (3). A region centered 1...

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Section: Neurofibromatosis Type 1 (Nf1)mentioning

confidence: 99%

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Hirayama

Kobayashi

Mizuguchi

et al. 2013

Molecular & Cellular Proteomics

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“…1 is one of the most common autosomal dominantly inherited disorders, with an incidence of about 1 in 3500 individuals (1). The NF1 hallmark is the development of benign tumors of the peripheral nervous system and the increased risk of developing malignancies.…”

Section: Neurofibromatosis Type 1 (Nf1)mentioning

confidence: 99%

Neurofibromatosis Type I Tumor Suppressor Neurofibromin Regulates Neuronal Differentiation via Its GTPase-activating Protein Function toward Ras

Yunoue

Tokuo

Fukunaga

et al. 2003

Journal of Biological Chemistry

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Neurofibromin, the neurofibromatosis type 1 (NF1) gene product, contains a central domain homologous to a family of proteins known as Ras-GTPase-activating proteins (Ras-GAPs), which function as negative regulators of Ras. The loss of neurofibromin function has been thought to be implicated in the abnormal regulation of Ras in NF1-related pathogenesis. In this study, we found a novel role of neurofibromin in neuronal differentiation in conjunction with the regulation of Ras activity via its GAP-related domain (GRD) in neuronal cells. In PC12 cells, time-dependent increases in the GAP activity of cellular neurofibromin (NF1-GAP) were detected after NGF stimulation, which were correlated with the down-regulation of Ras activity during neurite elongation. Interestingly, the NF1-GAP increase was due to the induction of alternative splicing of NF1-GRD type I triggered by the NGF-induced Ras activation. Dominantnegative (DN) forms of NF1-GRD type I significantly inhibited the neurite extension of PC12 cells via regulation of the Ras state. NF1-GRD-DN also reduced axonal and dendritic branching/extension of rat embryonic hippocampal neurons. These results demonstrate that the mutual regulation of Ras and NF1-GAP is essential for normal neuronal differentiation and that abnormal regulation in neuronal cells may be implicated in NF1-related learning and memory disturbance. Neurofibromatosis type 1 (NF1)1 is one of the most common autosomal dominantly inherited disorders, with an incidence of about 1 in 3500 individuals (1). The NF1 hallmark is the development of benign tumors of the peripheral nervous system and the increased risk of developing malignancies. The NF1 phenotype is highly variable; it affects several organ systems, including bones, skin, irises, and central nervous system manifested as gliomas and learning disabilities. The NF1 gene lies on chromosome 17q11.2 and encodes neurofibromin, a large 2818-amino acid protein (2). Since the majority of NF1 gene mutations frequently found in NF1 patients prevent intact neurofibromin expression, functional disruption of neurofibromin is potentially relevant to the expression of some or all of the multiple abnormalities that occur in NF1 patients (3).A region centered around the 360 amino acids encoded by the NF1 gene shows significant homology to the known catalytic domains of mammalian Ras GTPase-activating protein (p120GAP) and is also similar to yeast IRA1/2 proteins, which interact with Ras and mediate hydrolysis of Ras-bound GTP to GDP, resulting in Ras protein inactivation. The GAP-related domain of the NF1 gene product (NF1-GRD) also stimulates Ras GTPase and consequently inactivates Ras protein (4, 5).Two different isoforms, type I and type II, which are formed by alternative splicing, have been identified in the NF1-GRD region. Type II contains an additional 63-bp insertion (exon 23a) that encodes 21 amino acids in the center of NF1-GRD type I (6). The specific expression patterns of the two isoforms have been studied in several organs and cells (7,8) and pro...

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“…12). A prototypical example of the latter occurs in neurofibromatosis type 1 (NF1), an autosomal inherited disease with a 1:3,000 prevalence (13). The hallmark of NF1 is the neurofibroma, a peripheral nerve benign tumor comprised of transformed Schwann cells (14).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic Reversion of Invasive Neurofibromin-Deficient Schwannoma by FTS: Ras Inhibition Reduces BMP4/Erk/Smad Signaling

Barkan

Kloog

Ehrlich

2011

Molecular Cancer Therapeutics

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Linkage studies with chromosome 17 DNA markers in 45 neurofibromatosis 1 families

Cited by 25 publications

References 8 publications

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Neurofibromatosis Type I Tumor Suppressor Neurofibromin Regulates Neuronal Differentiation via Its GTPase-activating Protein Function toward Ras

Phenotypic Reversion of Invasive Neurofibromin-Deficient Schwannoma by FTS: Ras Inhibition Reduces BMP4/Erk/Smad Signaling

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