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Dissertation
Stable reintroduction of wild-type P53 causes the induction of growth arrest, apoptosis and an islet-like differentiation in a human pancreatic ductal carcinoma cell line
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
Aug 1998
DOI:
https://doi.org/10.17918/00009584
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death in the industrialized world, and has among the poorest prognosis of any malignancy. Mutations or alterations in the p53 tumor suppressor gene/protein are observed in 50% to 70% of these cancers, yet little information is available regarding the phenotypic effects of restoration of wild-type (wt) p53 function in pancreatic ductal carcinoma cells. The consequences of stable reintroduction of wtp53 on apoptosis and differentiation were examined in a poorly differentiated pancreatic carcinoma cell line (Panc-1), possessing only mutant (mt) p53 (codon 273 mutation. Stable expression of wt p53 caused G1 growth arrest (as shown by flow cytometry and BrdU labeling), and induced either apoptosis or a surviving population with an altered phenotype. The percentage of p53-induced cells to undergo apoptosis could be directly correlated to the levels of zinc used to induce the Mtmp53ts clones. The higher the level of wtp53 protein, the higher the levels of apoptotic cell death, as shown by immunoprecipitation and Western analysis. Electron microscopy revealed a presumptive altered secretory pattern with both an increased number and polarization of secretory vesicles, as well as the presence of extensive vacuoles that may be neurosecretory in nature. A panel of neuroendocrine/islet, ductal, and acinar differentiation markers were examined by RT-PCR, Western blotting, and immunohistochemistry. These ultrastructural and expression data provide evidence of a wtp53-induced neuroendocrine differentiation which may lead to an islet-like phenotype. This cell system may aid in the study of gene therapy for cancer, as well as provide a model for pancreatic islet cell differentiation. (Abstract shortened by UMI.).
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Details
- Title
- Stable reintroduction of wild-type P53 causes the induction of growth arrest, apoptosis and an islet-like differentiation in a human pancreatic ductal carcinoma cell line
- Creators
- Deborah Lang
- Contributors
- Bruce A. Ruggeri (Advisor) - Drexel University, Allegheny University of the Health Sciences (1996-1998)
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- xi, 158 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Allegheny University of the Health Sciences (1996-1998); School of Medicine (1996-1998); Pathology (and Laboratory Medicine) [Historical]
- Other Identifier
- 991021888828304721