p120 binds and is thought to regulate the cell-cell adhesion molecule E-cadherin. Experiments in a p120-deficient carcinoma cell line suggest a critical role for p120 in stabilizing E-cadherin. p120 downregulation occurs in a wide range of cancers and frequently correlates with E-cadherin loss. Thus I hypothesized that p120 is necessary for maintaining normal cadherin levels and that p120 loss may be a causal event leading to E-cadherin loss in tumors. To test this hypothesis, I knocked down p120 in vitro using siRNA and conditionally knocked out p120 in vivo using MMTV-Cre. My in vitro data demonstrate that p120 is essential for control of E-cadherin stability at the membrane and suggest that without p120, E-cadherin undergoes endocytosis and is degraded. By knocking out p120 in vivo with MMTV-Cre, I had intended to assess the effects of p120 loss on mammary tumorigenesis. Surprisingly, MMTV-Cre-mediated deletion of p120 led to postnatal lethality. Fortunately, MMTV-Cre is also expressed in the salivary gland, which is an excellent model system to study the effects of p120 ablation on glandular morphogenesis and development. As in vitro, p120 loss caused significant downregulation of E-cadherin. Concomitant with p120 loss, I observed premature dilation of salivary ducts and sporadic lack of cell polarity. As p120-null salivary glands developed, ducts extend and branch abnormally and acini do not develop, and indicating that p120 is critical to epithelial morphogenesis. Although these animals did not live long enough to develop cancer, they developed lesions that bore hallmarks of neoplasias including hyperplasia, loss of polarity, loss of cell-cell adhesion, and nuclear crowding. Together, these data reveal an essential role for p120 in regulating E-cadherin function and glandular morphogenesis, and they strongly support my hypothesis that p120 is a tumor modifier and/or suppressor.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-04012005-151452 |
| Date | 08 April 2005 |
| Creators | Davis, Michael Alan |
| Contributors | Albert B. Reynolds, Lynn M. M. Matrisian, Carlos Arteaga, Christopher Wright, Josiane Eid, Robert Whitehead |
| 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-04012005-151452/ |
| 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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