Dysregulation of the Notch signaling pathway plays an important role in lung cancer pathobiology. The Notch3 receptor is overexpressed in ∼40% of resected non-small cell lung cancers, and its suppression results in loss of the malignant phenotype both in vitro and in vivo. In this dissertation, I have identified novel ligand binding regions in the Notch3 receptor using a high throughput system and a Notch3 peptide library that spans the extrcellular domain. This knowledge allowed me to generated Fc-fusion proteins and neutralizing monoclonal antibodies to target these regions in the Notch3 receptor thereby interfering with signaling by blocking the interaction of the receptor with its ligands. In addition, I explored the roles of Jagged1, a Notch ligand, in lung cancer. I demonstrate that Jagged1 has the paradoxical roles of increasing cell growth and suppressing migration. Interestingly, this appears to be through a noncanonical, CSL-independent mechanism. The findings of these studies not only give novel insights into Notch3 signaling but also establish a foundation on which targeted therapies can be developed.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11012011-164959 |
| Date | 08 November 2011 |
| Creators | Lin, Luping |
| Contributors | Barbara Fingleton, Harold Moses, Martin Egli, David Carbone |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-11012011-164959/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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