The undetectable or reduced level of neurofibromin in the tumours obtained from neurofibromatosis type 1 patients suggests that this deficiency is closely related to their tumourigenesis.
Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors.
Coinactivation of the TP53 gene by deletion, or by point mutation along with NF1 gene inactivation, is known to exacerbate disease symptoms in NF1, therefore TP53 gene inactivation was screened.
The molecular basis of neurofibroma development in NF1 is loss of expression of the NF1 gene and its gene product, neurofibromin, resulting in elevated levels of Ras-guanosine triphosphate.
Since none of the clinically healthy relatives showing serum mitogenic activity was positive for the NF1 mutation analysis and, conversely, those having altered exons 31 or 32 of NF1 gene did not show any mitogenic activity; these results suggest that the phenotype expression of NF1 might depend not only on the NF1 mutations per se, but also on other genetic or epigenetic factors, such as serum glial proliferating molecules.
The finding of preserved NF1 gene expression in the non-NF1-related Triton tumor suggests that different genetic events predispose to the development of this rare neoplasm in sporadic cases.
We show that FTS treatment shortened the relatively long duration of Ras activation and signaling to extracellular signal-regulated kinase, Akt, and RalA in all NF1-deficient MPNST cell lines (NF1 cells) to that observed in a non-NF1, normally expressing neurofibromin MPNST cell line.
Our results provide in vivo support for the importance of the exon definition model during NF1 splicing, and suggest that the NF1 region containing exons 11 and 12a plays an important role in the activity of neurofibromin.
The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.
Here we show that expression of neurofibromin GRD, but not the p120GAP GRD, restores normal growth and cytokine signaling in three lineages of primary Nf1-deficient cells that have been implicated in the pathogenesis of neurofibromatosis type 1 (NF1).
To explain the observation that transgenic mice expressing the human T-lymphotropic virus type 1 (HTLV-1) tax gene under the control of the viral regulatory element also develop multiple neurofibromas, we demonstrate that the Tax trans-regulator can functionally repress NF1 gene expression through a cis-acting element located immediately upstream of its transcriptional start site, thereby allowing the development of benign neurofibromas without the need for direct mutations in NF1.
Given that haploinsufficiency of the NF1 gene product neurofibromin is responsible for some of the clinical manifestations, variations in expression of the wildtype NF1 allele might modify the phenotype.
We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas.
Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling.
These data implicate NF1 protein as a tumor suppressor gene product that negatively regulates p21ras and define a "positive" growth role for ras activity in NF1 malignancies.
We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs.
Individuals with neurofibromatosis 1 present with abnormalities of both astrocytes and neurons that result from reduced or absent expression of the NF1 gene product neurofibromin.
We also show that NF1 deficient neuroblastomas show only moderately elevated ras-GTP levels, in contrast to NF1 tumour cells, indicating that neurofibromin contributes differently to the negative regulation of ras in different cell types.