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Organ-specific, carcinogen-induced increases in cell proliferation in p53-deficient mice
1Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., First Department of Pathology, Osaka City University Medical School, Osaka, Japan. sukata@sc.sumitomo-chem.co.jp
Abstract:
Transgenic mice with germ-line p53 alleles disrupted by gene targeting are sensitive to the development of some spontaneous tumors and have provided researchers with much information with respect to cancer. In the present study, to cast light on the organ specificity of chemically induced carcinogenesis, we evaluated carcinogen-induced cell proliferation in target organs in heterozygote p53 knockout mice (p53-deficient mice). Groups of 9- or 10-week-old wild-type(+/+) and p53-deficient mice were respectively treated with one of the following carcinogens for 4 weeks: N-butyl-N-(4-hydroxybutyl)nitrosamine (0.0075% in drinking water); dimethylnitrosamine (0.001% in drinking water); dihydroxy-di-N-propylnitrosamine (0.1% in drinking water); 1,2-dimethylhydrazine (10 mg/kg body weight s.c. injection once a week); 4-nitroquinoline 1-oxide (4-NQO, 10 mg/kg b.w. s.c. injection once a week); or 7,12-dimethylbenz(a)anthracene (25 microg/kg body weight dermal application once a week). Cell proliferation was evaluated by measuring the 5-bromo-2'-deoxyuridine labeling indices in each target organ. The p53 and p21 statuses were evaluated by comparing the expressions of p53 protein, p21waf1/cip1 mRNA, and p21waf1/cip1 protein between the mice. 5-Bromo-2'-deoxyuridine labeling indices of the urinary bladder and the skin were significantly increased in p53-deficient mice as compared with the wild-type(+/+) mice. In the all organs examined, carcinogen-induced p21waf1/cip1 mRNA overexpression was detected with levels obviously lower in the p53-deficient animals. These data suggest that p53-deficient mice have an organ-specific increased sensitivity to the induction of cell proliferation in the urinary bladder and the skin. These are the same organs for which sensitivity to carcinogenesis has been reported. Because a decrease of p21waf1/cip1 protein overexpression was also observed in the organs in which cell proliferation did not appreciably differ from the level in wild-type(+/+) mice, this decrease might have no effect on sensitivity to cell proliferation and carcinogenesis. Alternatively, it might play an important role in the cell cycle regulation of only the sensitive organs.
Insights
Mice lacking the p53 gene show increased cell proliferation in the urinary bladder and skin after carcinogen exposure. This suggests p53 deficiency leads to organ-specific sensitivity to chemical carcinogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The tumor suppressor protein p53 plays a critical role in preventing cancer by regulating cell cycle arrest and apoptosis.
- Germ-line p53 knockout mice are models for studying cancer development and chemocarcinogenesis.
- Understanding organ-specific responses to carcinogens in p53-deficient models is crucial for cancer research.
Purpose of the Study:
- To investigate the organ specificity of chemically induced carcinogenesis in p53-deficient mice.
- To evaluate carcinogen-induced cell proliferation in target organs of wild-type and p53-deficient mice.
- To elucidate the role of p53 and p21 in mediating responses to chemical carcinogens.
Main Methods:
- Exposure of wild-type and p53-deficient mice to various chemical carcinogens (N-butyl-N-(4-hydroxybutyl)nitrosamine, dimethylnitrosamine, dihydroxy-di-N-propylnitrosamine, 1,2-dimethylhydrazine, 4-nitroquinoline 1-oxide, 7,12-dimethylbenz(a)anthracene).
- Assessment of cell proliferation using 5-bromo-2'-deoxyuridine labeling indices in target organs.
- Evaluation of p53 and p21 expression levels (protein and mRNA) in different tissues.
Main Results:
- Significantly increased cell proliferation (5-bromo-2'-deoxyuridine labeling indices) was observed in the urinary bladder and skin of p53-deficient mice compared to wild-type controls.
- Carcinogen-induced p21waf1/cip1 mRNA overexpression was detected at lower levels in p53-deficient animals across all examined organs.
- A decrease in p21waf1/cip1 protein overexpression was noted in organs where cell proliferation did not differ significantly between genotypes.
Conclusions:
- p53-deficient mice exhibit organ-specific increased sensitivity to carcinogen-induced cell proliferation, particularly in the urinary bladder and skin.
- The observed decrease in p21waf1/cip1 expression in p53-deficient mice may contribute to this heightened sensitivity in specific organs.
- These findings highlight the critical role of p53 in regulating cell cycle and preventing carcinogenesis in an organ-dependent manner.