A porcine model of neurofibromatosis type 1 that mimics the human disease (original) (raw)
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RAS and beyond: the many faces of the neurofibromatosis type 1 protein
Disease Models & Mechanisms, 2022
Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the cloning of the NF1 gene and the recognition that the encoded protein, neurofibromin, largely functions as a negative regulator of RAS activity, attention has mainly focused on RAS and canonical RAS effector pathway signaling relevant to disease pathogenesis and treatment. However, as neurofibromin is a large cytoplasmic protein the RAS regulatory domain of which occupies only 10% of its entire coding sequence, both canonical and non-canonical RAS pathway modulation, as well as the existence of potential non-RAS functions, are becoming apparent. In this Special article, we discuss our current understanding of neurofibromin function.
Journal of Biological Chemistry, 1995
The neurofibromatosis type 1 (NF1) gene encodes a protein, neurofibromin, containing GTPase-activating protein-related domain (GRD) that stimulates intrinsic GTPase activity of Ras protein. By screening a randomly mutagenized NF1-GRD library in Saccharomyces cerevisiae, we isolated two NF1-GRD mutants (NF201 and NF204) with single amino acid substitutions, which suppress the heat shock-sensitive phenotype of the RAS2(G19V) mutant. The NF1-GRD mutants also suppress the oncogenic Ras-induced transformation of NIH 3T3 mouse fibroblasts (Nakafuku, M.
Neurofibromatosis 1: closing the GAP between mice and men
Current Opinion in Genetics & Development, 2003
Neuro®bromatosis 1 (NF1) is a common genetic condition in which affected individuals are prone to the development of benign and malignant tumors. The NF1 tumor suppressor encodes a protein product, neuro®bromin, which functions in part as a negative regulator of RAS. Loss of neuro®bromin expression in NF1-associated tumors or Nf1-de®cient mouse cells is associated with elevated RAS activity and increased cell proliferation. Despite this straightforward pathophysiologic association between neuro®bromin, RAS, and tumorigenesis, recent insights from mouse and Drosophila modeling studies have suggested additional functions for neuro®bromin and have implicated Nf1 heterozygosity in tumor formation. Lastly, Nf1 knockout mouse studies have also demonstrated important roles for cooperating genetic changes that accelerate tumorigenesis as well as modi®er genes that impact on cancer susceptibility.
Journal of Investigative Dermatology, 2000
suppressor gene product, neurofibromin, functions in part as a Ras-GAP, a negative regulator of Ras. Neurofibromin is implicated in the neuronal abnormality of NF1 patients; however, the precise cellular function of neurofibromin has yet to be clarified. Using proteomic strategies, we identified a set of neurofibromin-associating cellular proteins, including axon regulator Collapsin response mediator protein-2 (CRMP-2). CRMP-2 directly bound to the C-terminal domain of neurofibromin, and this association was regulated by the manner of CRMP-2 phosphorylation. In nerve growth factor (NGF)-stimulated PC12 cells, neurofibromin and CRMP-2 co-localized particularly on the distal tips and branches of extended neurites. Suppression of neurofibromin using NF1 siRNA significantly inhibited this neurite outgrowth and upregulated a series of CRMP-2 phosphorylations by kinases identified as CDK5, GSK-3b and Rho-kinase (RhoK).
An anti-Ras function of neurofibromatosis type 2 gene product (NF2/Merlin)
The Journal of biological chemistry, 1994
Previously, we have cloned a candidate for the 595-amino acid neurofibromatosis type 2 tumor suppressor called NF2 or Merlin, with striking sequence similarity in its N-terminal half to an F-actin-binding protein family called TERM, which includes talin, ezrin, radixin, and moesin (Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Kley, N., Menon, A. G., Pulaski, K., Haase, V. H., Ambrose, C. M., Munro, D., Bove, C., Haines, J. L., Martuza, R. L., MacDonald, M. E., Seizinger, B. R., Short, M. P., Buckler, A. J., and Gusella, J. F. (1993) Cell 72, 791-800). In an attempt to determine whether NF2 serves as a tumor suppressor and if so whether its N-terminal half is involved in its anti-oncogenicity, both full-length NF2 and its N-terminal half (NF2-N, residues 9-359) have been expressed in v-Ha-Ras-transformed NIH/3T3 cells. Like neurofibromatosis type 1 (NF1) fragments (Nur-E-Kamal, M. S. A., Varga, M., and Maruta, H. (1993) ...
Journal of Biological Chemistry, 2008
suppressor gene product, neurofibromin, functions in part as a Ras-GAP, a negative regulator of Ras. Neurofibromin is implicated in the neuronal abnormality of NF1 patients; however, the precise cellular function of neurofibromin has yet to be clarified. Using proteomic strategies, we identified a set of neurofibromin-associating cellular proteins, including axon regulator Collapsin response mediator protein-2 (CRMP-2). CRMP-2 directly bound to the C-terminal domain of neurofibromin, and this association was regulated by the manner of CRMP-2 phosphorylation. In nerve growth factor (NGF)-stimulated PC12 cells, neurofibromin and CRMP-2 co-localized particularly on the distal tips and branches of extended neurites. Suppression of neurofibromin using NF1 siRNA significantly inhibited this neurite outgrowth and upregulated a series of CRMP-2 phosphorylations by kinases identified as CDK5, GSK-3b and Rho-kinase (RhoK).
Mouse Models of Neurofibromatosis 1 and 2
Neoplasia, 2002
The neurofibromatoses represent two of the most common inherited tumor predisposition syndromes affecting the nervous system. Individuals with neurofibromatosis 1 (NF1) are prone to the development of astrocytomas and peripheral nerve sheath tumors whereas those affected with neurofibromatosis 2 (NF2) develop schwannomas and meningiomas. The development of traditional homozygous knockout mice has provided insights into the roles of the NF1 and NF2 genes during development and in differentiation, but has been less instructive regarding the contribution of NF1 and NF2 dysfunction to the pathogenesis of specific benign and malignant tumors. Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors.
Mouse tumor model for neurofibromatosis type 1
Science
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by increased incidence of benign and malignant tumors of neural crest origin. Mutations that activate the protooncogene ras, such as loss of Nf1, cooperate with inactivating mutations at the p53 tumor suppressor gene during malignant transformation. One hundred percent of mice harboring null Nf1 and p53 alleles in cis synergize to develop soft tissue sarcomas between 3 and 7 months of age. These sarcomas exhibit loss of heterozygosity at both gene loci and express phenotypic traits characteristic of neural crest derivatives and human NF1 malignancies. Mutations in tumor suppressor genes are common events in human cancers (1). Individuals with a mutation in one copy of the NF1 gene develop benign cutaneous neurofibromas, plexiform neurofibromas, café-au-lait spots, and axillary freckling (2). Through loss of heterozygosity (LOH) at the NF1 locus, patients with neurofibromatosis type 1 are at increased risk of developing malignancies of neural crest derivatives, including malignant peripheral nerve sheath tumors (MPNSTs), malignant Triton tumors (MTTs), and pheochromocytomas (2,3). MPNSTs and MTTs arise from plexiform neurofibromas and frequently are associated with mutation or loss of the p53 tumor suppressor gene (2,4). The protein product of the NF1 gene neurofibromin is a guanosine triphosphatase (GTPase)activating protein (GAP) that can negatively regulate p21ras signaling (5). Mutations that activate Ras cooperate with mutations that inactivate p53 in a number of transformation assays and models of tumorigenesis (6). The Nf1 and p53 genes are linked in humans and in mice (7). To determine whether null mutations in Nf1 and p53 cooperate to accelerate tumorigenesis in vivo, we generated a recombinant mouse strain harboring inactivated Nf1 and p53 alleles linked on mouse chromosome 11. We accomplished this with intercrosses of trans-Nf1 +/− :p53 +/− compound heterozygotes or through crosses with p53 +/− heterozygotes. The integrity of the recombinant cis-Nf1:p53 chromosome was established by genomic Southern blot analysis and by polymerase chain reaction (PCR). All progeny of cis-Nf1 +/− :p53 +/− test crosses to wild-type animals were either compound heterozygotes or entirely wild type, which confirms the integrity of the double-mutant chromosome.