Characterizing the role of the p53/p63 target gene, Perp, in epidermal homeostasis and cancer
Abstract/Contents
- Abstract
- Desmosomes are multi-protein cell-cell adhesion junctions found throughout stratified squamous epithelia and the myocardium. These specialized adhesion complexes maintain the structural integrity of these tissues, which are continuously exposed to mechanical stress. Perturbations in desmosome structure and function lead to clinical symptoms associated with a variety of human skin and heart disorders. While the molecular basis for these phenotypes is mainly attributable to the role of the desmosome in resisting mechanical stress, emerging roles for this complex in cellular signaling, apoptosis, and tissue morphogenesis are accumulating. Understanding the molecular mechanisms of desmosome function in both normal tissue homeostasis and disease will bring new insights into these complex biological processes. Loss of cellular adhesion junctions is a common feature of epithelial cancer progression. However, the specific contribution of how desmosome function affects this disease has not been looked at in great detail. In the first two chapters, we examined the consequences of desmosome loss to tumor formation using mice deficient for the desmosomal protein Perp. In-depth analyses focusing on Perp's mechanism of action revealed new insights into the role of Perp and the desmosome in adhesion, apoptosis, and inflammation. In the second part of my thesis, we investigated the role of the desmosome in epithelial wound healing and in Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC), a human skin disease characterized by severe craniofacial abnormalities, skin erosions, and alopecia. We first showed that proper desmosome function is essential for efficient wound healing in vivo. Lastly, we investigated whether some of the clinical symptoms associated with AEC were attributable to defects in Perp function. We identified a subset of AEC derived p63 mutants that were capable of transactiving Perp expression, despite being previously characterized as inactive for other p63 target genes. Analysis of skin biopsies revealed disrupted Perp expression in a subset of AEC patients, further corroborating a role for Perp dysfunction in the pathogenesis of this disease. Together these studies have uncovered important roles for Perp and the desmosome in maintaining proper skin homeostasis and insights into the mechanisms of how Perp loss and desmosome disruption contributes to disease progression in a variety of contexts.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Beaudry, Veronica Graciela |
|---|---|
| Associated with | Stanford University, Program in Cancer Biology. |
| Primary advisor | Attardi, Laura |
| Thesis advisor | Attardi, Laura |
| Thesis advisor | Nelson, W. J. (W. James) |
| Thesis advisor | Oro, Anthony, 1958- |
| Thesis advisor | Sage, Julien |
| Advisor | Nelson, W. J. (W. James) |
| Advisor | Oro, Anthony, 1958- |
| Advisor | Sage, Julien |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Veronica Graciela Beaudry. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Ph.D. Stanford University 2010 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Veronica Graciela Beaudry
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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