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Title: The roles of p53 in hepatocytes
Author: Bellamy, Christopher O. C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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p53-deficiency was silent in normal liver and did not affect progression from diploidy to polyploidy in the ageing liver. However, in primary culture the absence of p53 resulted in increased hepatocyte proliferation indices and decreased sensitivity to proliferation inhibition by TGFβ. Moreover, p53-deficient cells continued to survive and proliferate under conditions of minimal trophic support that led to growth arrest and apoptosis of wild type cells. In vivo, p53-deficient mice had enhanced proliferative responses to both xenobiotic hepatomitogen and CCl4-induced liver necrosis, although lack of persistent proliferation showed that other control mechanisms are important. There was no simple relationship between p53 and apoptosis following DNA damage, since uv irradiation led to p53-independent apoptosis, even though p53 was stabilized and transcriptionally activated - as assessed with a transiently transfected p53-specific reporter plasmid. By contrast, γ-irradiation injury to hepatocytes failed to produce detectable changes in either p53 immunopositivitiy or transcriptional transactivation activity. Nevertheless, p53 did couple both uv and γ-irradiation injury to growth arrest, showing that agents producing different forms of DNA damage can act differently through p53, yet produce a common biological response. The observation has implications for how particular dysfunctional mutations of p53 in carcinogenesis could alter hepatocyte responses to different DNA injuries. Thus p53 becomes important when hepatocytes are released from G0 and stressed, sensitizing them to mitogen and cytokine regulators of cell cycle progression and apoptosis. Hence p53 deficiency is likely to be significant in an environment of persistent regenerative stimuli and unfavorable trophic support, or in the presence of other enabling genetic lesions. This model is relevant to human hepatocarcinogenesis, which almost always occurs against a background of chronic hepatocellular destruction in hepatitis and cirrhosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available