- Targeting Cellular Signaling Pathways to Inhibit the Growth of NF1 Tumors
- Many Types of NF1 Mutations Can Lead to the Development of Tumors in NF1 Patients
- Elucidating the Relationship between Learning Deficits and the NF1 Gene
- Elucidating the Functions of the Nf2 Gene
Targeting Cellular Signaling Pathways to Inhibit the Growth of NF1 Tumors
Posted December 19, 2002
Raymond Mattingly, Ph.D., Wayne State University
Individuals with type I neurofibromatosis (NF1) often develop malignant tumors called neurofibrosarcomas. Currently, no therapy exists to prevent the occurrence of these tumors. Researchers at Wayne State University are finding that two pathways cells, used to signal to each other are involved in the development of neurofibrosarcomas in NF1 patients. More specifically, the pathways under investigation are the Ras and mitogen-activated protein (MAP) kinase signaling pathways. It has previously been shown that Ras can become continually activated in human tumors. This abnormal Ras activation can lead to uncontrolled cell growth and tumor formation through the activation of the MAP kinase pathway. To date, the researchers have identified an inhibitor of the MAP kinase pathway that decreases the ability of neurofibrosarcoma cells to grow in soft agar. Inhibitors developed in this study may be developed into drugs that are less toxic and more specific for NF1-related tumors, and could thus be used in clinical trials to prevent tumor formation or to treat existing tumors.
Publications:
Mattingly RR, Gibbs RA, Menard RE, Reiners JJ Jr. 2002. Potent suppression of the proliferation of A10 vascular smooth muscle cells by combined treatment with lovastatin and 3-allylfarnesol, an inhibitor of protein farnesyltransferase. J. Pharmacol. Exp. Ther. 303: 74-81.
Mattingly RR, Milstein ML, Mirkin BL. 2001. Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells. Cellular Signaling 13:499-505.
Link:
Abstract: Signal Transduction Targets for Pharmacological Intervention in Type I Neurofibromatosis
Many Types of NF1 Mutations Can Lead to the Development of Tumors in NF1 Patients
Posted June 24, 2002
Bruce Korf, M.D., Ph.D., Harvard-Partners Center for Genetics and Genomics; Lin Kluwe, Ph.D., University Hospital Hamburg-Eppendorf, Germany
Neurofibromatosis 1 (NF1) is a genetic disease caused by mutations in the NF1 gene. Nearly one-third of NF1 patients develop tumors called plexiform neurofibromas. These tumors occur in a variety of shapes and sizes and can become very large. Dr. Bruce Korf at the Harvard-Partners Center for Genetics and Genomics, in collaboration with researchers at several other universities, screened 42 NF1 patients from 41 families with plexiform neurofibromas for mutations in the NF1 gene. Mutations in genes come in a number of types - nonsense, frameshift, splicing, and missense. Dr. Korf and his colleagues found the aforementioned types of mutations in the NF1 gene in the patients they examined. They found that there was no correlation between the type of NF1 mutation and the size, location, or feature of plexiform neurofibromas. This finding suggests that there is no specific type of NF1 mutation that leads to the development of plexiform neurofibromas.
Publications:
Kluwe L, Friedrich RE, Korf B, Fahsold R, and Mautner V-F. 2002. NF1 mutations in neurofibromatosis 1 patients with plexiform neurofibromas. Human Mutation 19(3):309-313.
Link:
Abstract: Natural History of Plexiform Neurofibromas in NF1
For more information on Dr. Korf's study see http://www.partners.org
Elucidating the Relationship between Learning Deficits and the NF1 Gene
Posted March 19, 2002
Camilynn Brannan, Ph.D., University of Florida, Gainesville
Neurofibromatosis 1 (NF1) is a commonly inherited genetic disorder caused by mutations in the NF1 gene. Symptoms include the presence of neurofibromas (benign tumors that can become malignant), café au lait spots (pigmented lesions on the skin), Lisch nodules of the iris, and a wide range of learning disabilities. Camilynn Brannan and her colleagues at the University of Florida, Gainesville, are studying neurofibromin, which is the protein produced by the NF1 gene. The NF1 gene encodes two distinct forms of neurofibromin: types I and II. Dr. Brannan and her colleagues generated mice lacking neurofibromin type II and demonstrated that the mice developed normally and did not have an increased predisposition to tumor formation. However, they found that these mice as adults (between the ages of 4 and 13 months) had specific impairments in spatial learning, contextual discrimination, and motor coordination. The results from this novel mouse model suggest that the learning deficits in NF1 patients could result from the disruption of neurofibromin type II function. Ultimately, this study may lead to the development of a treatment for the learning disabilities associated with NF1.
Publications:
Costa, RM, Yang T, Huynh DP, Pulst SM, Viskochil DH, Silva AJ, and Brannan CI. 2001. Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. Nature Genetics 27(4):399-405.
Link:
Abstract: Dissection of the Pathogenesis of Neurofibromatosis Type 1- Associated Myeloid Leukemia
Elucidating the Functions of the Nf2 Gene
Posted January 14, 2002
Channing Der, Ph.D., University of North Carolina at Chapel Hill
Neurofibromatosis includes two distinct genetic disorders affecting the nervous system, neurofibromatosis 1 and neurofibromatosis 2. Neurofibromatosis 2 is characterized by the growth of tumors on nerves of the inner ear, among other complications. Individuals with neurofibromatosis 2 have a mutated Nf2 gene. The mutated Nf2 gene's inability to control genes and proteins involved in cell growth appears to lead to tumor development. Researchers at the University of North Carolina at Chapel Hill are studying the normal Nf2 gene's effect on Ras and Rac, two proteins involved in regulating cell growth. They found that the Nf2 gene strongly inhibited Ras and Rac functioning in cultured cells. In addition, the Nf2 gene inhibited Rac-induced formation of colonies in soft agar (a sign that cells have become cancerous). Results from this study suggest that the development of tumors in neurofibromatosis 2 patients may be due to a mutated Nf2 gene's inability to inhibit Ras and Rac functioning.
Publications:
Shaw RJ, Paez JG, Curto M, Yaktine A, Pruitt WM, Saotome I, O'Bryan JP, Gupta V, Ratner N, Der CJ, Jacks T, McClatchey AI. 2001. The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Developmental Cell 1(1):63-72.
Links:Abstract: Role of NF1 and NF2 in Signaling and Transformation