Download Free Characterization Of P53 Tumor Suppressor Pathway In Mouse Colon Epithelial Cells And Azoxymethane Induced Colon Tumor Book in PDF and EPUB Free Download. You can read online Characterization Of P53 Tumor Suppressor Pathway In Mouse Colon Epithelial Cells And Azoxymethane Induced Colon Tumor and write the review.

The current year (2004) marks the Silver Anniversary of the discovery of the p53 tumor suppressor. The emerging ?eld ?rst considered p53 as a viral antigen and then as an oncogene that cooperates with activated ras in transforming primary cells in culture. Fueling the concept of p53 acting as a transforming factor, p53 expression was markedly elevated in various transformed and tumorigenic cell lines when compared to normal cells. In a simple twist of fate, most of the studies conducted in those early years inadvertently relied on a point mutant of p53 that had been cloned from a normal mouse genomic library. A bona ?de wild-type p53 cDNA was subsequently isolated, ironically, from a mouse teratocarcinoma cell line. A decade after its discovery, p53 was shown to be a tumor suppressor that protects against cancer. It is now recognized that approximately half of all human tumors arise due to mutations within the p53 gene. As remarkable as this number may seem, it signi?cantly underrepresents how often the p53 pathway is targeted during tumorigenesis. It is my personal view, as well as many in the p53 ?eld, that the p53-signaling pathway is corrupted in nearly 100% of tumors. If you are interested in understanding cancer and how it develops, you must begin by studying p53 and its pathway. After demonstrating that p53 functions as a tumor suppressor the ?eld exploded and p53 became a major focus of scientists around the world.
The p53 tumor suppressor protein reacts to a number of genotoxic and oncogenic signals. Upon activation, p53 can promote various cellular processes including cell cycle arrest, differentiation, and apoptosis via its ability to regulate the transcription of target genes. In this thesis, two of these genes, c-myc and klhl26, were examined for their regulation and physiological significance to the p53 pathway. c-myc is repressed in a number of mouse and human cell types in a p53-dependent manner. p53 binds to the c-myc gene and mediates transrepression through a mechanism that involves historic deacetylation. This repression is required for the efficient induction of G1 cell cycle arrest and differentiation by p53. As cell cycle regulation is believed to be a mechanism by which p53 mediates tumor suppression, the transcriptional repression of c-myc by p53 may restrain tumor development. In contrast to c-myc, klhl26 is transcriptionally-activated by p53. This is also associated with the binding of p53 to the klhl26 gene. klhl26 possesses prosurvival activity and confers cytoprotection against both p53-dependent and p53-independent apoptosis. The significance of this antiapoptotic function to the p53 response, however, is presently unclear. Taken together, c-myc and klhl26 are bona fide p53 target genes and their regulation impacts upon the ability of p53 to mediate various processes in the cell.
One of the most frequent alterations in breast cancer is deregulation of the p53 tumor suppression signaling pathways. The tumor suppressor p53 is a sequence-specific transcription factor that is activated in response to various cellular stresses. It has been predicted that there are over 1500 consensus p53 binding sites present in the human genome. However, only a subset of p53 binding sites and correlated target genes have been identified to date, and characterization of p53 signaling pathways in their entirety is not yet complete. The goal of this study is to further define and characterize such pathways through the identification of novel genes that are directly regulated by p53. Using chromatin immunoprecipitation followed by a yeast selection system we have isolated over 100 genomic DNA fragments that contain novel p53 binding sites. The new DNA fragments obtained have been mapped to various regions of the human genome, and four novel p53 target genes have been identified and validated. This research will lead to a more complete understanding of p53-regulated signaling pathways in mammary epithelial cells.