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NF1 (Neurofibromatosis Type 1) Greg Hogan Ribbon Representation of NF1-333 Scheffzek, et al. (The EMBO Journal Vol. 17,pp. 4313-4327, 1998) Structural analysis of the GAP-related domain from neurofibromin and its implications
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Neurofibromatosis Type 1 a.k.a. - peripheral neurofibromatosis - von Recklinghausen’s disease prevalence ~ 1/3500 inherited in autosomal dominant fashion fully penetrant in adults NF1 has one of highest single locus mutation rates known in humans
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Common Signs of Neurofibromatosis Type 1 http://www.ctf.org/
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1.The NF1 Gene and Protein Product Neurofibromin 2.Nf1 Knockout Mice 3.Role of Neurofibromin in Cancer NF1
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The NF1 Gene and Protein Product Neurofibromin NF1 gene identified by positional cloning in 1990 NF1 gene found to encode neurofibromin BLAST Fig. 1a, Dasgupta and Gutmann
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Human NF1 yeast Ira Lodish, Fig. 9-31
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Proposed Binding of Ras to NF1 Scheffzek, et al. (The EMBO Journal Vol. 17,pp. 4313-4327, 1998) Structural analysis of the GAP-related domain from neurofibromin and its implications
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Fig. 1b, Dasgupta and Gutmann
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Loss of Neurofibromin Fig. 2. Gutmann
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Mice Knockouts Nf1 -/- mutantsNf1 -/- mutants –Die in utero between embryonic days 12.5 and 13.5 Death is result of cardiac vessel defect Also exhibit neural tube closure defects Mice Knockouts
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Nf1 +/- mutantsNf1 +/- mutants –Are cancer prone (generally, die by month 15) Do not develop hallmark NF1 cancers (neurofibromas, astrocytomas) Develop leukemia and pheochromocytomas –Exhibit cell-autonomous growth advantage –Exhibit increased # of abnormal astrocytes Nf1 +/- astrocytes have increased RAS pathway activation –Nf1 +/- cell phenotypes reversed by introduction of wild-type NF1-GAP domain or by directly inhibiting RAS or RAS pathway molecules Mice Knockouts
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Nf1 +/- ; p53 +/- mutantsNf1 +/- ; p53 +/- mutants –Develop high-grade sarcomas with features of human MPNSTs (malignant peripheral nerve sheath tumors) Mice Knockouts
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Pathways to Tumor Development Fig. 2. b,c Dasgupta and Gutmann
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Pathways to Tumor Development Fig. 2. a Dasgupta and Gutmann
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Take Home Messages NF1 tumor suppressor encodes a protein product neurofibromin Neurofibromin functions as a negative regulator of RAS Neurofibromin loss can lead to the development of various type of tumors
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potential target for therapy Fig. 3.a Reed and Gutmann
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Mutations Deletions Insertions Subsitutions Possible gene conversion between non- homologous pseudogene and NF1 80% of new NF1 mutations are of paternal origin
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