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Title: Inactivation of the p53 and p21 (cip1/waf1/sdi1) genes in normal human cells
Author: Brown, J. P. St. L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1998
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The p53 gene is an important gene because it is mutated in approximately 50-60% of cancers and plays a key role in the regulation of cell division. An important gene which can be regulated by the p53 gene is the p21 (cip1/waf/sdi1) gene. To determine which functions of the p53 gene required the p21 gene, I inactivated both copies of the p21 gene in normal human cells. Loss of the p21 gene by homologous recombination increased the proliferative life span of normal human cells, which have a limited life span in culture. These experiments were the first in which both copies of a gene have been altered in normal human cells by homologous recombination. I showed that homologous recombination can also be used to efficiently alter the p53 gene in normal human cells. I also have data which suggests that the efficiency of homologous recombination, using vectors made from DNA from one individual, is not significantly different when performed in the cells from that same individual or in cells from an unrelated individual. As inactivation of the p21 gene increased the proliferative capacity of human cells you might expect this to increase the frequency of malignancy as the cells could undergo additional cell divisions and therefore have a greater chance of accumulating sufficient mutations to develop malignancy. To address the issue I examined whether other functions of the p53 gene, such as genetic stability and the apoptotic pathway, were intact. In the cells in which both copies of the p21 gene had been inactivated by homologous recombination, genetic stability was preserved and the apopotitic pathway was enhanced.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available