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p53 deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage
Author(s) -
Bellamy Christopher O. C.,
Clarke Alan R.,
Wyllie Andrew H.,
Harrison David J.
Publication year - 1997
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.11.7.9212083
Subject(s) - apoptosis , biology , dna damage , cell cycle , cell growth , cancer research , hepatocyte , cell cycle checkpoint , mitosis , microbiology and biotechnology , programmed cell death , immunology , in vitro , dna , genetics
Despite good evidence for p53 dysfunction in human hepatocellular carcinomas, little is known of the significance of p53 to normal hepatocytes and whether p53 dysfunction is relevant to early hepatocarcinogenesis. We have therefore examined the consequences of targeted p53 deficiency in hepatocytes for regulation of apoptosis, proliferation, and ploidy. p53 deficiency was silent in normal liver and did not affect progression from diploidy to polyploidy in the aging 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 CCl 4 ‐induced liver necrosis, although lack of persistent proliferation showed that other control mechanisms are important. There was no simple relationship between p53 and apoptosis after DNA damage because UV irradiation led to p53‐independent apoptosis, even though p53 was stabilized. However, p53 did couple DNA damage to growth arrest, and abnormal mitoses after γ‐irradiation of regenerating p53 null livers demonstrated circumstances where loss of G 1 and G 2 checkpoints may generate abnormal ploidy. Thus p53 becomes important when hepatocytes are released from G 0 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. In that context, by reducing the need for cytokine support and disabling DNA damage‐induced growth arrest, p53 deficiency should facilitate the expansion of preneoplastic clones in chronic liver disease.—Bellamy, C. O. C., Clarke, A. R., Wyllie, A. H., Harrison, D.J. p53 deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage. FASEB J. 11, 591–599 (1997)