Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

Qin, Xiusheng; Liu, Huan; Gerson, Stanton L.

doi:10.1038/sj.onc.1202798

Cited by 36 publications

(18 citation statements)

References 34 publications

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“…The loss of the FOXN1 transcription factor may contribute to neoplasia in mice. Mismatch repair-deficient mice treated with genotoxic exposure have accelerated onset of lymphogenesis (37)(38)(39), also supporting the idea that in the constitutive absence of mismatch repair, mice are poised to develop predominantly hematologic malignancies, whether spontaneous or induced.…”

Section: Discussionmentioning

confidence: 58%

A Lack of DNA Mismatch Repair on an Athymic Murine Background Predisposes to Hematologic Malignancy

Campbell

Nation²,

Andrew

2005

Cancer Research

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Inheritance of a germline mutation in one of the DNA mismatch repair genes predisposes human individuals to hereditary nonpolyposis colorectal cancer, characterized by development of tumors predominantly in the colon, endometrium, and gastrointestinal tract. Mice heterozygous for a mismatch repair-null mutation generally do not have an increased risk of neoplasia. However, mice constitutively lacking mismatch repair are prone to tumor development from an early age, particularly thymic lymphomas. Mismatch repair-deficient mice crossed to Apc +

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Section: Discussionmentioning

confidence: 58%

A Lack of DNA Mismatch Repair on an Athymic Murine Background Predisposes to Hematologic Malignancy

Campbell

Nation²,

Andrew

2005

Cancer Research

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“…Methyl adducts on DNA also evoke DNA strand breaks through abortive mismatch-repair process. 30) In addition, formaldehyde induces genetic alterations, such as sister chromatid exchanges and micronuclei formation. 31,32) MAM is also conjugated to glucuronate by detoxification enzymes in the liver.…”

Section: Discussionmentioning

confidence: 99%

Parp‐1 deficiency implicated in colon and liver tumorigenesis induced by azoxymethane

et al. 2003

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he polyADP-ribosylation reaction is catalyzed by poly(ADP-ribose) polymerase (Parp) family proteins using NAD as a substrate. Parp-1 is a 113-kDa nuclear enzyme which polyADP-ribosylates various nuclear proteins, including Parp-1 itself and histones, after activation by binding to DNA single and double strand breaks. Parp-1 −/− cells show delayed DNA rejoining after treatment with alkylating agents, and a role of Parp-1 in base excision repair and double strand break (DSB) repair has been suggested. 1) Parp-1 −/− cells also display enhanced genomic instability, including chromosome aberration and increased levels of micronuclei formation both in the absence of DNA damage and after DNA damage introduction. 2, 3)In addition, Parp-1 also has a leading role in cell death after DNA damage and Parp-1 overactivation. NAD depletion after DNA damage was abrogated in Parp-1 −/− cells and as a consequence, Parp-1 −/− cells became resistant to cell death induced by severe DNA damage. [4][5][6][7][8] This evidence suggests that loss of Parp-1 function could have a substantial contribution to tumorigenesis, through the introduction of genetic alterations.In fact, we previously demonstrated that Parp-1 −/− mice, harboring exon 1 disruption in Parp-1, showed increased incidences of liver and lung tumors after N-nitrosobis(2-hydroxypropyl)amine administration. Tong et al. 13) It is also known that pharmacological intakes of niacin augment NAD level and increase the latency of the ethylnitrosourea-induced liver carcinogenesis.14) Since Parp-1 is also involved in the transcriptional regulation of various genes, [15][16][17] the impact of Parp-1 deficiency may differ among various types of tumors and among various organs. Therefore, the effect of Parp-1 deficiency on tumorigenesis needs to be investigated in various models of tumorigenesis.In the present study, Parp-1 −/− mice, harboring exon 1 disruption of Parp-1, were treated with azoxymethane (AOM), a potent colon carcinogen. We observed that the Parp-1 −/− mice showed an enhanced incidence of tumor development in the colon and also in the liver. Colon tumors induced by AOM in rodents are frequently associated with alteration of the Wnt-β-catenin signaling cascade, and β-catenin accumulation is observed.18) Therefore, to examine whether the development of tumors in Parp-1 +/+ and Parp-1 −/− mice involves alteration of Wnt-β-catenin signaling, immunostaining of β-catenin was carried out. Materials and Methods Parp-1−/− mice generated by disrupting the Parp-1 exon 1 through the insertion of a neomycin resistance gene cassette 5) were used in this study. Mice were housed in plastic cages in an air-conditioned room with a 12 h light-dark cycle. Water and basal diet (CE-2, CLEA JAPAN, Tokyo) were available ad libitum. Parp-1 +/+ and Parp-1 −/− female mice (7-8 weeks old) of a mixed genetic background of ICR and 129Sv were produced by line-breeding. The mean body weights of Parp-1 + / + and Parp-1 −/− mice at the start of the experiment were 21.7±1.7 g and 21.4±2.9 g, respectively. P...

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“…We showed that MGMT blocked the carcinogenic eect of MNU in mice de®cient in the DNA repair gene PMS2 (Qin et al, 1999a) and in mice transgenic for LMO1 (Allay et al, 1997), a gene which is associated with T-cell lymphomas in humans and transgenic mice (McGuire et al, 1992;Neale et al, 1995) through transcriptional activation of genes regulating T-cell development and proliferation.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of human O6-alkylguanine DNA alkyltransferase (AGT) prevents MNU induced lymphomas in heterozygous p53 deficient mice

2001

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-alkylguanine DNA alkyltransferase (AGT) is a key mechanism in the prevention against MNU induced malignant transformation by removal of O 6 methyl guanine (O 6 mG) adducts. We asked whether heterozygous p53 de®cient mice (p53+/7) would be more susceptible to MNU induced lymphomas than wild type mice, and whether O 6 mG adducts were responsible for this susceptibility. To determine whether MGMT overexpression would be protective, p53+/7 mice were bred to human MGMT transgenic mice (MGMT+) and treated with 50 mg/kg MNU. MNU increased the incidence of thymic lymphomas in non-transgenic p53+/7 mice from 23% (n=13) to 68% (n=22) and decreased the mean latency from 433 to 106 days (P=0.01 compared to untreated mice). Wild type mice had an incidence of 30% (n=38) and a mean latency of 135 days after MNU. Overexpression of MGMT in the thymus of p53+/7 mice signi®cantly reduced the lymphoma incidence from 68 to 28% (n=17) and increased the latency from 106 to 167 days (P=0.003). Similarly, the lymphoma incidence in MGMT+/wild type mice decreased from 30 to 8% (n=12) and the latency increased to 297 days (P=0.2). Loss of the wild type allele was found in only 2/17 lymphomas occurring in p53+/7 mice and there were no signi®cant point mutations in exons 5 ± 8 of p53. Furthermore, there was no loss of p53 function in these mice. These data demonstrate that unrepaired O 6 mG lesions act cooperatively with the reduced p53 dose and lead to lymphomagenesis in p53+/7 mice, but AGT overexpression and rapid removal of O 6 mG adducts is protective. Oncogene (2001) 20, 5258 ± 5263.

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Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

Cited by 36 publications

References 34 publications

A Lack of DNA Mismatch Repair on an Athymic Murine Background Predisposes to Hematologic Malignancy

A Lack of DNA Mismatch Repair on an Athymic Murine Background Predisposes to Hematologic Malignancy

Parp‐1 deficiency implicated in colon and liver tumorigenesis induced by azoxymethane

Overexpression of human O6-alkylguanine DNA alkyltransferase (AGT) prevents MNU induced lymphomas in heterozygous p53 deficient mice

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