Markovics, Jennifer Ann
(2006)
The roles of the Rb and p53 tumor suppressor pathways in an intestinal tumorigenesis model system.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cancer is characterized by unregulated growth. SV40 large tumor (T) antigen interacts with cellular proteins to cause transformation and tumors in rodents. Interaction with the retinoblastoma (Rb) family of tumor suppressors allows T antigen to inhibit growth arrest, while T antigen interaction with the p53 tumor suppressor blocks apoptosis.Transgenic mice that express T antigen (TAgwt) in intestinal enterocytes develop hyperplasia that progresses to dysplasia. Expression of a mutant of T antigen (TAg3213) that is unable to interact with Rb family members in enterocytes does not result in an intestinal phenotype. Thus, T antigen interaction with Rb family members (pRb, p130 and p107) is required for T antigen-induced intestinal neoplasia. pRb performs the majority of its tumor suppressive properties through repression of E2Fs, a family of transcription factors that regulate the expression of many genes required for S phase. T antigen binds Rb family members, disrupts p130/E2F complexes and induces E2F2 and E2F3a in villi. These E2Fs are bound to the promoters of up-regulated E2F-responsive genes, supporting a role for them in T antigen-induced hyperplasia. Expression of an amino-terminal truncation mutant of T antigen (TAgdl1137) in villi enterocytes is sufficient to induce hyperplasia, but not progression to dysplasia. We hypothesized the T antigen interaction with p53 is required for the progression to dysplasia. However, T antigen does not bind and stabilize p53 in villi enterocytes. Furthermore, TAgdl1137/p53-/- mice do not progress to dysplasia. Therefore, we propose that the p53 is not active in intestinal enterocytes and its inactivation is not required for T antigen-induced progression to dysplasia.These results suggest that distinct tumor suppressor proteins and pathways function in specific cell types to regulate normal or abnormal mechanisms of proliferation.
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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
24 March 2006 |
| Date Type: |
Completion |
| Defense Date: |
1 November 2005 |
| Approval Date: |
24 March 2006 |
| Submission Date: |
25 November 2005 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Biological Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
E2F; intestinal epithelium; mouse model; neoplasia; p53; pRb; retinoblastoma; SV40 T antigen; tumorigenesis |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-11252005-161822/, etd-11252005-161822 |
| Date Deposited: |
10 Nov 2011 20:06 |
| Last Modified: |
15 Nov 2016 13:52 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9796 |
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