The role of Neurofibromatosis Type 1 in Schwann Cell development and tumor formation and the influence of steroid hormones.
dc.contributor.author | Roth, Therese Mary | en_US |
dc.date.accessioned | 2008-01-16T15:06:43Z | |
dc.date.available | 2008-01-16T15:06:43Z | |
dc.date.issued | 2007 | en_US |
dc.date.submitted | 2007 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/57616 | |
dc.description.abstract | The Neurofibromatosis Type 1 (NF1) gene functions as a tumor suppressor gene. One known NF1 function is to turn off the p21ras pathway by accelerating Ras hydrolyzation of active rasGTP to inactive rasGDP. Loss of neurofibromin (the protein product) in the autosomal dominant disorder NF1 is associated with tumors of the peripheral nervous system, particularly neurofibromas in which the major cell type is the Schwann Cell (SC). We have developed an in vitro system for differentiating mouse embryonic stem cells (mESC) that are NF1 wild type (+/+), heterozygous (+/-), or null (-/-) into SC-like cells to study the role of NF1 in SC development and tumor formation. These SC-like cells, regardless of their NF1 status, express SC markers appropriate for their developmental stage, and support and preferentially direct neurite outgrowth from primary embryonic neurons. They are also capable of expressing myelin proteins. NF1 null and heterozygous SC-like cells proliferate at an accelerated rate compared to NF1 wild type; this growth advantage can be reverted to wild type levels using a Mek inhibitor The mESC of all NF1 types can also be differentiated into neuron-like cells. The behavior and genetic repertoires of the cells under different developmental conditions can be compared, providing an ideal paradigm for studies of the role of NF1 in cell growth and differentiation of the different cell types affected by NF1. The number and size of neurofibromas in NF1 patients has been shown to increase during pregnancy. SC-like differentiated mESC with varying levels of neurofibromin and NF1 tumor cell lines derived from a malignant and a benign human tumor, were used to study proliferation in response to hormones. Estrogen and androgen receptors showed very low/no expression in the NF1+/+ cells, low levels of expression in NF1+/- cells, and high levels of expression in NF1-/- cells. We have also found that an E2 metabolite, 2Methoxyestradiol, is cytotoxic to the NF1-/- malignant tumor cell line, and inhibits proliferation in the other cell lines. 2ME2 or its derivatives could provide new treatment avenues for NF1 hormone-sensitive tumors at times of greatest hormonal influence. | en_US |
dc.format.extent | 1373 bytes | |
dc.format.extent | 3901387 bytes | |
dc.format.mimetype | text/plain | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en_US | en_US |
dc.subject | Neurofibromatosis Type 1 (NF1) | en_US |
dc.subject | Steroid Hormones | en_US |
dc.subject | Pregnancy | en_US |
dc.subject | Schwann Cells | en_US |
dc.subject | Neurofibromin | en_US |
dc.subject | Mouse Embryonic Stem Cells (MES Cells) | en_US |
dc.title | The role of Neurofibromatosis Type 1 in Schwann Cell development and tumor formation and the influence of steroid hormones. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Cell and Developmental Biology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Barald, Kate F. | en_US |
dc.contributor.committeemember | Hammer, Gary D. | en_US |
dc.contributor.committeemember | Krull, Catherine E. | en_US |
dc.contributor.committeemember | Robins, Diane M. | en_US |
dc.contributor.committeemember | Zhu, Yuan | en_US |
dc.subject.hlbsecondlevel | Neurosciences | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/57616/2/rotht_1.pdf | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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