Absence of <i>p53</i> mutations and various frequencies of ki‐ras exon 1 mutations in rat hepatic tumors induced by different carcinogens

Tokusashi, Yoshihiko; Fukuda, Ikue; Ogawa, Katsuhiro

doi:10.1002/mc.2940100108

Cited by 30 publications

(8 citation statements)

References 29 publications

(22 reference statements)

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“…This situation is critical, since it may lead to an enhanced frequency of mutation and eventually, to the transformation of healthy cells to a malignant form. This study also provides a partial explanation for the low incidence of p53 mutations reported for a number of tumors developed in experimental animals by exposure to potent chemical carcinogens [32, 33, 34]. …”

Section: Discussionmentioning

confidence: 95%

Lack of p53-Mediated G1 Arrest in Response to an Environmental Carcinogen

Khan¹,

Vousden

Dipple³

1999

Oncology

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The environmental carcinogen, 5-methylchrysene, is a component of cigarette smoke. Its reactive metabolite, anti-5-methylchrysene-1,2-dihydrodiol-3,4-epoxide (5-MeCDE) mainly reacts with the N²-position of guanine residues in the DNA molecule. In this study, we demonstrate that the tumor suppressor protein p53 is stabilized in response to DNA damage by 5-MeCDE but fails to induce the cells’ protective mechanism of G1 arrest in the human breast carcinoma cell line, MCF-7. In contrast, actinomycin D treatment of these cells did lead to G1 arrest. Western analyses revealed that, though both actinomycin D and 5-MeCDE treatment stabilized p53, only trace levels of p21^waf1/cip1 were seen in the latter case. This lack of p21^waf1/cip1 expression in 5-MeCDE-treated cells is attributed to a stealth characteristic of this environmental carcinogen that allows it to damage DNA and still escape the p53-mediated cellular defense mechanism of G1 arrest.

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Section: Discussionmentioning

confidence: 95%

Lack of p53-Mediated G1 Arrest in Response to an Environmental Carcinogen

Khan¹,

Vousden

Dipple³

1999

Oncology

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“…Although the expression of mdr1 is highly activated, mutation of p53 does not always occur during hepatocarcinogenesis, at least in its early stage of liver tumor development (54). In addition, it has been known that the mdr1b expression in rat liver can be rapidly activated by chemical carcinogens such as 2-AAF and aflatoxin B1 (12,13), however, in rat hepatocellular carcinomas induced by these carcinogens, p53 mutations do not always occur (55,56). More importantly, van Gijssel et al (57) recently reported that p53 activity can be also induced by 2-AAF and aflatoxin B1 in rat liver.…”

Section: P53-mediated Regulation Of Rat Mdr1b Expressionmentioning

confidence: 99%

Wild-type p53-mediated Induction of Rat mdr1bExpression by the Anticancer Drug Daunorubicin

Zhou

Kuo

1998

Journal of Biological Chemistry

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The expression of P-glycoproteins encoded by the mdr gene family is associated with the emergence of the multidrug resistance phenotype in animal cells. mdr expression can be induced by many extracellular stimulants including cytotoxic drugs and chemical carcinogens. However, little is known about the mechanisms involved. Here, we report that the expression of the rat mdr1b can be induced by anticancer drug daunorubicin. Further analysis identified a bona fide p53-binding site spanning from base pairs ؊199 to ؊180 (5-GAACATGTA-GAGACATGTCT-3) in the rat mdr1b promoter that is essential for basal and daunorubicin-inducible promoter activities. In addition, our results show that wildtype p53 can up-regulate not only the promoter function but also endogenous expression of the rat mdr1b. To the best of our knowledge, this is the first report showing that a specific p53-binding site is involved in the transcriptional regulation of mdr gene by wild-type p53. Since p53 is a sensor for a wide variety of genotoxic stresses, our finding has broad implications for understanding the mechanisms involved in the inducible expression of mdr gene by anticancer drugs, chemical carcinogens, UV light, and other DNA-damaging agents.

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“…For example, N-nitrosomethylurea (NMU) induces rat mammary adenocarcinomas containing GGA-GAA transitions at codon 12 of Haras, whereas CAA-CTA transversion at codon 61 has been found in mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) [32]. Several studies have reported K-ras gene mutations in chemically induced liver tumors; the gene mutations were found at codon 12 in AFB1-induced HCCs, at codon 13 in benzo[a]pyrene-induced liver tumor, and at codon 61 in trichloroacetic acid-induced liver tumors [33][34][35][36][37][38]. In the present study, although we did not confirm whether or not the mutation of codon 64 can activate the K-ras gene using synthetic constructs, we observed 100% of HCCs and 100% mutation of the codon 64 in the HCCs samples induced by BLM þ 1-NP.…”

Section: Discussionmentioning

confidence: 99%

Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by bleomycin and 1-nitropyrene in A/J mice

Bai

Nakanishi

Takayama

et al. 2003

Teratog. Carcinog. Mutagen.

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Bleomycin is a radiomimetic antitumor agent with unique genotoxic properties. 1-nitropyrene is an environmental mutagen and carcinogen that undergoes both oxidative and reductive metabolism. In the present study, hepatocellular carcinomas were induced in male A/J mice by the intraperitoneal injection of bleomycin (120 mg/kg) followed by the intraperitoneal administration of 1-nitropyrene (total dose: 1,575 mg/kg). In order to understand the mechanism by which these two compounds induce hepatocellular carcinomas, the incidence and spectrum of mutations in the K-ras proto-oncogene in these hepatocellular carcinomas were analyzed. The hepatocellular carcinomas were induced by the administration of bleomycin and 1-nitropyrene were evaluated for point mutations in exon 1 and exon 2 of the K-ras gene by the polymerase chain reaction and a sequencing analysis. No mutation was found in the hotspots regions of the K-ras gene codon 12, 13, or 61. However, the codon 64 of the K-ras gene mutation was identified in 10 of 10 (100%) hepatocellular carcinomas. All mutations showed the same pattern, which was TAC-CAC transition. Codon 64 of the K-ras gene mutation may thus play an important role in the induction of hepatocellular carcinomas by bleomycin in the existence of 1-nitropyrene. As far as we know, this is the first report of a codon 64 mutation in the K-ras gene in a chemically induced tumor.

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Absence of p53 mutations and various frequencies of ki‐ras exon 1 mutations in rat hepatic tumors induced by different carcinogens

Cited by 30 publications

References 29 publications

Lack of p53-Mediated G1 Arrest in Response to an Environmental Carcinogen

Lack of p53-Mediated G1 Arrest in Response to an Environmental Carcinogen

Wild-type p53-mediated Induction of Rat mdr1bExpression by the Anticancer Drug Daunorubicin

Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by bleomycin and 1-nitropyrene in A/J mice

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