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NF1: Tumor Suppressor Gene

NF1: Tumor Suppressor Gene. Presentation by Hana Masood. Overview of Presentation. Disease – Neurofibromatosis Type I NF1 Gene Protein - Neurofibromin Protein Function – RasGAP Biological Role – Active in Ras Pathway NF1 gene and Neurofibromin Role in Cancer. Neurofibromatosis Type I.

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NF1: Tumor Suppressor Gene

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  1. NF1: Tumor Suppressor Gene Presentation by Hana Masood

  2. Overview of Presentation • Disease – Neurofibromatosis Type I • NF1 Gene • Protein - Neurofibromin • Protein Function – RasGAP • Biological Role – Active in Ras Pathway • NF1 gene and Neurofibromin Role in Cancer

  3. Neurofibromatosis Type I • Among most common neurogenetic disorders -It is heritable; all affected members of family have same form of NF • Affects 1 in 3,500 • Whereas NF2 affects only 1 in 40,000 • Diagnosis based on any 2 of the following clinical criteria: - Greater than or equal to 6 café-au-lait spots - Freckles underarm or groin - Greater than or equal to 2 neurofibromas, or 1 plexiform neurofibroma - Iris Lisch nodules identified by ophthalmologist - Tumor of optic nerve called optic pathway glioma (in astrocytes) - Bone deformities (i.e. around eye, tibia) - First degree relative (parent, sibling, or child) http://www.understandingnf1.org/id/int_id_win.html

  4. Affects peripheral nerves brain, and spinal cord More active as get older In adolescence, also find learning disabilities in reading, math, trouble following directions, and paying attention All racial and ethnic backgrounds Symptoms vary person to person Neurofibromatosis Type I European Genetics Foundation http://www.charite.de/ch/medgen/eumedis/embryology04/neurocutan-disorders.html http://www.understandingnf1.org/exp/int_exp_wcn.html

  5. NF1 is a tumor suppressor gene NF1 is located on Chromosome 17 long arm - NF2 on other hand is located on Chromosome 22 NF1 gene encodes the protein Neurofibromin NF1 Gene http://www.charite.de/ch/medgen/eumedis/embryology04/neurocutan-disorders.html

  6. NF1 Gene • Cloned in 1990 • Over 300kb of genomic DNA, 50 exons • Very large and complicated, and genetic changes can be very small and subtle • A missense mutation in GAP-Related Domain is one way NF1 is inactivated - usually a mutation that causes a charge inversion; mostly change from Lysine to something like Glutamine in protein Scheffzek et al, The Embo Journal, 1998, Vol. 17 cc.oulu.fi/~anatwww/ NF/Neurofibromin/Ras.jpg

  7. NF1 Gene Inactivation (Loss of Function) • 50% of cases inherited from parent, other 50% of cases start out as a new NF1 mutation in sperm or egg that makes the child • All cell types are initially NF+/- until a subpopulation of Schwann cells undergo LOH and become NF-/- • Bi-allelic inactivation in Schwann cells causes the lack of expression of Neurofibromin protein - Schwann cells are the initiating cells in neurofibroma formation • So, NF1 behaves as a dominant trait phenotypically, but is still recessive genotypically Harrisingh and Lloyd, Cell Cycle, 2004, Vol. 3, p. e69 http://www.understandingnf1.org/id/int_id_win.html

  8. Biochemical and Cell Biological Role of Neurofibromin • Neurofibromin acts as a RasGAP that acts mostly in Schwann cells - What is a RasGAP? Lodish et al. Fig. 20-22

  9. Neurofibromin Molecule RasGAP (250-400 AA) 2818 • Has homology to p120GAP • Expressed in all tissues, highest levels in brain, kidney, and spleen • Associates with cytokeratin bundles in human keratinocytes and also binds tubulin • Thus, exerts its effects in part by controlling organization of cytoskeleton during the formation of cellular contacts cc.oulu.fi/~anatwww/ NF/Neurofibromin/Ras.jpg

  10. Neurofibromin GAP-Related Domain http://www.nature.com/emboj/journal/v17/n15/full/7591132a.html Scheffzek et al, The Embo Journal, 1998, Vol. 17

  11. Neurofibromin GAP-Related Domain and Ras Interaction http://www.nature.com/emboj/journal/v17/n15/full/7591132a.html Scheffzek et al, The Embo Journal, 1998, Vol. 17

  12. Neurofibromin in Ras Pathway cc.oulu.fi/~anatwww/ NF/Neurofibromin/Ras.jpg

  13. Neurofibromin involvement in Schwann cells – Biological Role • Neurofibromin involved in Schwann cell differentiation • Schwann cells are a regenerative cell typethat has no known stem-cell population • Part of peripheral nerves http://fig.cox.miami.edu/~cmallery/150/neuro/sf42x10b.jpg

  14. Schwann Cells http://www.unis.org/UNIScienceNet/Schwann%20cell.jpg http://www.bu.edu/histology/i/21301loa.jpg

  15. Biological Role of Neurofibromin • Following nerve damage, myelinating Schwann cells produce new cells by de-differentiating, proliferating, and then re-differentiating • Axons in vivo provide signals that regulate Schwann cell differentiation • Ras causes de-differentiation and leads to proliferation, and then Neurofibromin RasGAP causes re-differentiation of Schwann cells Harrisingh and Lloyd, Cell Cycle, 2004, Vol. 3, p. e69, 2004

  16. NF1 inactivation causes constitutive Ras activity in Schwann cells Ras signalling drives the de-differentiation of myelinating Schwann cells that lead to tumors if uncontrolled Thus, the role of Neurofibromin is to act as a tumor suppressor and control Ras activity by catalyzing its inactivation when necessary Biological Role of Neurofibromin Harrisingh and Lloyd, Cell Cycle, 2004, Vol. 3, p. e69-70, 2004

  17. Biological Role of Neurofibromin – Studies • NF1 bi-allelic inactivation is embryonically lethal in mice • NF1-/- Schwann cells are angiogenic and invasive in vitro, and have: - elevated levels of Ras-GTP (active) compared to wild-type cells - altered morphology elongated and hyper-refractile, long processes • NF1+/- Schwann cells have intermediate phenotype (some Neurofibromin activity) Harrisingh and Lloyd, Cell Cycle, 2004, Vol. 3, p. e69-70, 2004

  18. Summary of Biological Role of Neurofibromin • Ras pathway in Schwann cell acts by driving the de-differentiation process itself, not by blocking a differentiation signal • The Raf/ERK signal can act dominantly over differentiation signals emanating from axons • Neurofibromin indirectly allows re-differentiation to happen by controlling the level of de-differentiation Harrisingh and Lloyd, Cell Cycle, 2004, Vol. 3, p. e70, 2004

  19. NF1+/- Schwann cells might not have sufficiently increased Ras signalling to de-differentiate But, state may make Schwann cells more susceptible to de-differentiation and facilitate loss of second allele (LOH) to shift equilibrium in favor of the de-differentiated state NF1 Inactivation Role in Cancer – De-Differentiation Harrisingh and Lloyd, Cell Cycle, 2004, Vol. 3, p. e70-71

  20. NF1-/- Schwann cells really induce neurofibroma formation in the presence of abnormal heterozygous NF1 environment that drive proliferation Haploinsufficient state of somatic tissue surrounding NF1 tumors initiates or progresses tumor formation When cellular environment has both functional NF1 alleles, the onset, growth potential, and multicullular nature of NF1-/- neurofibromas is suppressed NF1 Inactivation Role in Cancer – Nonautonomous Process Zhu et al, Science, 2002, Vol. 296, p. 920, 922

  21. NF1 Inactivation Role in Cancer – Nonautonomous Process • “Tumor formation is a coordinated process in which incipient tumor cells recruit collaborating cells (i.e. mast, fibroblast cells) from the environment” • Through heterozygous inactivation mouse study, believed that heterozygous mast cells interacting with nullizygous Schwann cells creates a cytokine-rich microenvironment permissive for tumor growth Zhu et al, Science, 2002, Vol. 296, p. 921-22

  22. NF1 Inactivation Role in Cancer – Nonautonomous Process • NF1+/- mice have abnormal responses to skin wounding, with increased collagen deposition and fibroblast proliferation, also observed in neurofibroma formation • NF+/- neurons, mast cells, and fibroblasts in mice do not undergo NF1 LOH, promote abnormal cell environment • NF+/- fibroblasts have defects in proliferation and perineurial sheath formation, allowing inappropriate exposure to circulating growth factors and hormone • NF-/- Schwann cells secrete increased levels of stem cell factor, thought to stimulate mast cell chemotaxis, which induces collagen deposition, cell proliferation, and angiogenesis Harrisingh and Lloyd, Cell Cycle, 2004, Vol. 3, p. e71, 2004

  23. NF1 Inactivation Role in Cancer - Overall • Nerve damage could trigger the production of proliferative signals by NF1+/- fibroblasts, nerve cells, and mast cells that could result in the unregulated proliferation of de-differentiated NF1-/- Schwann cells that have lost Neurofibromin activity • NF1 patients undergo an altered response to normal nerve repair signal with repeated cycles of attempted repair resulting in neurofibroma formation Harrisingh and Lloyd, Cell Cycle, 2004, Vol. 3, p. e70-1, 2004

  24. Role of the Inactivation of NF1 in Cancer (Neurofibromatosis) - Animation • Inactivation of NF1 in Cancer

  25. Neurofibromatosis Type I and Cancer • Neurofibromas – benign • Plexiform neurofibromas – subtype of benign tumors, can undergo transformation by CDKN2A/p16 or INK4A inactivation (causes loss of p16 cdk inhibitor) into malignant peripheral nerve sheath tumors (MPNSTs) • Also, MPNSTs aberrantly express EGFR • MPNSTs are highly aggressive cancers • 8-13% of NF1 patients develop it • 15-20% of NF1 children develop low-grade astrocytomas Arun and Gutmann, Current Opinion in Neurology, 2004, Vol. 17, p. 101 http://www.cancerindex.org/geneweb/NF1.htm#malig

  26. Neurofibromatosis Type I and Cancer • “NF1 patients developing malignant neoplasms can have any type of NF1 germline mutation such as a total gene deletion, a frameshift mutation, an in-frame deletion, or a missense mutation. We conclude that in our series no specific type of NF1 germline mutation was found in NF1 individuals with malignancies, but that large NF1 gene deletions were more frequently found in this group than reported for the general population of NF1 individuals.” Genes Chromosomes Cancer, Vol. 26, p. 376-80, 1999 European Genetics Foundation http://www.charite.de/ch/medgen/eumedis/embryology04/neurocutan-disorders.html

  27. What did the Elephant Man have? • Joseph Merrick did not have NF1 • He really had another disease  Proteus Syndrome (sine had mutation on another gene) Genetic Science Learning Center at the University of Utah http://gslc.genetics.utah.edu/units/disorders/nf1/elephantman.cfm

  28. Treatment for NF1 • Primary option is surgery for both benign and malignant tumors • Noncomparative phase II evaluation of cis-retinoic acid (promaturation agent) and interferon-alpha (anti-inflammatory and antiangiogenic effects) • Phase I studies for farnesyl protein transferase inhibitors that inhibit Ras activity • Pirfenidone, an antibiotic drug that regulates cytokine action, in clinical trial • EGFR inhibitors may be effective in MPNSTs • Possibly therapies that neutralize the effects of haploinsufficiency before the onset of tumorogenesis Arun and Gutmann, Current Opinion in Neurology, 2004, Vol. 17, p. 102, 104

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