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RAS SIGNALING IN SCHWANN CELL TUMOR FORMATION: NEUROFIBROMATOSIS TYPE 1

RANGWALA, FATIMA ABDULLA
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1069774794

Abstract Details

2003, PhD, University of Cincinnati, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience).
Patients with Neurofibromatosis Type 1 (NF1) carry a germline mutation in the NF1 gene and have an increased risk for developing a variety of benign and malignant tumors. Neurofibromin, the protein encoded by the NF1 gene, is a GTPase activating protein that negatively regulates Ras activity. NF1 -deficient tumors display elevated levels of Ras-GTP suggesting that inappropriate Ras activation contributes to tumor formation. While many abnormal phenotypes of NF1 mutant cells can be ascribed to H-, N-, and K-Ras-GTP excess, Ras-independent phenotypes have been described. The major objective of this work is to explore the contribution of Ras-dependent and Ras-independent signaling pathways to tumor formation in neurofibromin deficient cells. The first set of studies demonstrates that Schwann cells derived from Nf1 null mice have enhanced migration in comparison to wildtype controls. Nf1 -/- mouse Schwann cell migration is not reversed by inhibition of the classical Ras proteins, suggesting that migration is independent of their increased H-, N-, and/or K-Ras activation. We find that TC21/R-Ras2 and its downstream effectors play a role in the migration of neurofibromin-deficient Schwann cells. These studies are the first to implicate TC21 activity in benign tumor formation. The second set of studies investigates Ras signaling in the context of malignant transformation in NF1. NF1 patients are at a greater risk for the development of malignant peripheral nerve sheath tumors (MPNST) than the general population. We hypothesize that a NF1 -specific pathway contributes to the pathogenesis of NF1-associated MPNST. To better understand the molecular events involved in MPNST formation, we characterize 6 NF1-associated MPNST cell lines, 2 sporadic MPNST lines, and 7 normal human Schwann cell samples. We demonstrated that NF1-associated MPNSTs, but not sporadic MPNSTs, had elevated levels of Ras-GTP and loss of p16 INK4a expression. Ras-GTP levels of NF1-associated MPNSTs correlate with their rates of proliferation. In addition, we identify a molecular signature that distinguishes NF1-associated MPNSTs from sporadic MPNSTs. Taken together, these data reveal that each of the Ras isoforms contributes to different aspects of NF1 tumor formation.
Dr. Nancy Ratner (Advisor)
144 p.
neurofibromatosis Type 1; Schwann Cell; RAS; MPNST; microarray

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Citations

  • RANGWALA, F. A. (2003). RAS SIGNALING IN SCHWANN CELL TUMOR FORMATION: NEUROFIBROMATOSIS TYPE 1 [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1069774794

    APA Style (7th edition)

  • RANGWALA, FATIMA. RAS SIGNALING IN SCHWANN CELL TUMOR FORMATION: NEUROFIBROMATOSIS TYPE 1. 2003. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1069774794.

    MLA Style (8th edition)

  • RANGWALA, FATIMA. "RAS SIGNALING IN SCHWANN CELL TUMOR FORMATION: NEUROFIBROMATOSIS TYPE 1." Doctoral dissertation, University of Cincinnati, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1069774794

    Chicago Manual of Style (17th edition)

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© 2003, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.