Increased tumor cell proliferation in murine tumors with decreasing dosage of wild-typep53

Abstract

A number of transgenic animal model systems have addressed the mechanistic role of p53 loss in tumor progression. However, many of these tumor models have analyzed p53 function in the context of other transgenes expressing activated oncogenes or defective tumor suppressor genes generated by gene targeting. To examine the role of p53 loss independent of other exogenous oncogenic influences, we analyzed some of the biological aspects of tumor formation and progression in p53-knockout mice containing a null germline p53 allele. We analyzed tumors from p53-/-, p53+/-, and p53+/+ littermates. Some of the p53+/- tumors had lost the remaining p53 allele (p53+/- loss of heterozygosity), whereas others retained the allele (p53+/-). In this report, we show that loss or absence of p53 conferred a tumor growth advantage by increasing the rate of cellular proliferation in a p53 dosage-dependent manner. The apoptotic levels in tumor tissue were found to be modest and not significantly dependent on p53 status. These results contrast with those from some other p53-deficient tumor models, in which p53 loss was associated with more rapid tumor progression through abrogated apoptosis. Finally, as p53 has been shown to regulate certain angiogenic factors, we examined the levels of angiogenesis in p53-containing and p53-deficient tumors. We found no p53-dependent differences in the levels of tumor angiogenesis measured by intratumoral microvessel density.

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

“…Other studies have found that proliferation is increased in p53-deficient tumours. 22 We did not find an obvious effect of p53 status on proliferation or apoptosis in tumours. Our results support the idea that acceleration of tumorigenesis in p53 þ/-mice may be due to a gene-dosage effect and haploinsufficient phenotype, such that a second p53 LOH event is not required.…”

“…While some have found that loss of the wild-type allele of p53 was correlated with attenuated apoptosis and accelerated tumour growth, 2,3 other studies have failed to reveal a major role for p53 in modulating apoptosis in tumour. 22 Almost half (40%) …”

Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer

“…Similarly, TP53 ‐deleted HCT116 cells expressing only 25% of the normal p53 mRNA levels lost the ability to effectively induce p53‐responsive genes and apoptosis after exposure to ultraviolet radiation . Studies using mouse models have shown that transgenic mice carrying a heterozygous TP53 deletion developed more and larger mammary tumors than animals carrying two wild‐type TP53 alleles, that loss of both TP53 alleles is not a prerequisite for tumor formation, that mere reduction in p53 levels may be sufficient to promote tumorigenesis and that loss or absence of TP53 conferred a tumor growth advantage by increasing the rate of cellular proliferation in a p53 dosage‐dependent manner . Moreover, analysis of human cancers obtained from patients with the Li‐Fraumeni cancer susceptibility syndrome, which is characterized by germ line TP53 mutations, revealed that the remaining wild‐type TP53 allele is not always lost, suggesting that haploinsufficiency of TP53 may be sufficient for tumor initiation …”

Survival of irradiated recipient mice after transplantation of bone marrow from young, old and “early aging” mice

“…Early studies of the role of p53 in aging were hampered as mice lacking p53 (p53−/−) develop lethal tumors early in life [ 45 ]. However, Tyner et al demonstrated that mutant mice expressing a truncated form of p53 (designated as p53m or the m-allele), display a premature aging phenotype [ 6 ].…”