Roles of the Pas1 and Par2 genes in determination of the unique, intermediate susceptibility of BALB/cByJ mice to urethane-induction of lung carcinogenesis: Differential effects on tumor multiplicity, size and Kras2 mutations

Kasahara, Hidenori; Obata, Masahiko; Ogawa, Katsuhiro; Lee, Gang-Hong

doi:10.1038/sj.onc.1201357

Cited by 21 publications

(32 citation statements)

References 28 publications

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“…Linkage analysis and fine mapping in various mouse crosses and congenic mice have significantly narrowed the Par2 region (7)(8)(9)(10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

“…Par2 is mapped to the mouse chromosome 18 and accounts for 60% phenotype variance (7)(8)(9). The resistance of BALB/cJ mice appears due to the interaction between the Pas1 QTL and Par2 QTL in the BALB/cJ mouse genome (10). We previously used (A/J ϫ BALB/ cJ) ϫ BALB/cJ congenic mice to successfully fine map the Par2 locus into a candidate region encompassed by the D18Mit103 and D18Mit162 markers (11).…”

Section: Introductionmentioning

confidence: 99%

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Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia

Wang¹,

Devereux

Vikis

et al. 2004

Cancer Research

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In this study, we performed systematic candidate gene analyses of the Pulmonary adenoma resistance 2 locus. Differential gene expression in lung tissues and nucleotide polymorphisms in coding regions between A/J and BALB/cJ mice were examined using reverse transcription-PCR and direct sequencing. Although not all genes in the interval were analyzed at this moment due to the recent database updating, we have found that the Pol gene, encoding the DNA polymerase , contains 25 nucleotide polymorphisms in its coding region between A/J and BALB/cJ mice, resulting in a total of ten amino acid changes. Primer extension assays with purified BALB/cJ and A/J proteins in vitro demonstrate that both forms of Pol are active but that they may differ in substrate discrimination, which may affect the formation of Kras2 mutations in mouse lung tumors. Altered expression of POL protein and an amino acid-changing nucleotide polymorphism were observed in human lung cancer cells, suggesting a possible role in the development of lung cancer. Thus, our data support the Pol gene as a modifier of lung tumorigenesis by altering DNA polymerase activity.

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“…Linkage analysis and fine mapping in various mouse crosses and congenic mice have significantly narrowed the Par2 region (7)(8)(9)(10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia

Wang¹,

Devereux

Vikis

et al. 2004

Cancer Research

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“…Since the BALB Par2 has been shown to be a negative modi®er of Pas1 (Karasaki et al, 1997), positional cloning of these loci should disclose molecular mechanisms of genetically controlled tumor sensitivity, resistance and their interaction. It should also contribute to ®nding clues for a fundamental strategy of cancer prevention in man, because mouse and human genes are highly syntenic.…”

Section: Discussionmentioning

confidence: 99%

“…By analysing (C3H x BALB)F 1 x C3H backcross mice, we elucidated that BALB mice carry the A/J allele of Pas1 on chromosome 6, whose phenotypic expression is partly suppressed by the dominantly resistant Par2 locus on chromosome 18, resulting in their overall intermediate phenotype (Karasaki et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Fine chromosomal localization of the mouse Par2 gene that confers resistance against urethane-induction of pulmonary adenomas

2001

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BALB/cByJ mice are 14 times more resistant to urethaneinduction of pulmonary adenomas than the susceptible A/ J strain. Our previous linkage analysis of (A/J x BALB/ cByJ)F 1 x A/J backcross mice provided statistical evidence that a major resistance locus of BALB/cByJ with a dominant e ect, designated Par2 (Pulmonary adenoma resistance 2), exists within an approximately 25 cM section of distal chromosome 18. To facilitate molecular identi®cation of the Par2 locus, the present study was conducted to ®nely localize its chromosomal position utilizing Par2-congenic mice. Male BALB/cByJ mice were mated with female C57BL/6J mice carrying recessive Par2 alleles and their male F 1 progeny were backcrossed to female BALB/cByJ mice. A male backcross mouse heterozygous within the Par2 interval of 25 cM was randomly selected and again backcrossed to female BALB/cByJ mice. This backcross-selection cycle was simply repeated to produce semi-congenic mice with a general BALB/cByJ genetic background except for the Par2 interval, where the mice were heterozygous with paternal C57BL/6J alleles and maternal BALB/cByJ alleles. After the 6th or 7th backcross, nine male mice possessing a recombination within the paternal Par2 interval were retained and crossed to female A/J mice. Resultant progeny were treated with urethane and examined for lung tumor development in order to deduce the Par2 genotypes of the recombinants through linkage analysis. By comparing the deduced Par2 genotype of each recombinant with its recombinational breakpoint, the Par2 locus was con®ned to an approximately 0.5 cM region¯anked by D18Mit103 and D18Mit188 loci. Our results indicate that fully congenic mice conventionally established by at least nine simple backcrosses or by the speed congenic method are not necessarily required for ®ne mapping of quantitative trait loci. In the case of the Par2 locus, we found that semi-congenic mice after as few as four simple backcrosses were useful for this purpose. The map information obtained in this study should enable subsequent positional cloning of the Par2 gene. Oncogene (2001) 20, 3979 ± 3985.

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“…The tumor-resistant phenotype is unique for the BALB Par2 allele. While the C3H and B6 Par2 alleles are not phenotypically discernable from the A Par2 allele, by analysing (C3H Â BALB)F 1 Â C3H backcross mice, we elucidated that BALB mice carry the A allele of Pas1, whose phenotype is partly suppressed by the resistant BALB Par2 allele, resulting in an overall intermediate phenotype (Karasaki et al, 1997). Interestingly, the BALB Kras2 allele is also known to be K s .…”

Section: Oncogenomicsmentioning

confidence: 99%

Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2 (Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner: detection of polymorphisms in the Polı gene as a candidate for Par2

et al. 2003

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The Pulmonary adenoma resistance 2 (Par2) locus of the BALB/cByJ mouse, located within 0.5 cM of chromosome 18, is responsible for reducing the mean multiplicity of urethane-induced lung tumors relative to those in C57BL/ 6J, A/J and C3H/HeJ mice. Thus, BALB/B6-Par2 congenic strain genetically identical to BALB/cByJ except carrying C57BL/6J Par2 alleles develops seven times more tumors than BALB/cByJ. To gain clues for identification of Par2 candidate genes, we analysed lung tumorigenesis in BALB/cByJ2BALB.B6-Par2 chimeric animals. Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous. In addition, the BALB.B6-Par2-and BALB/cByJ-derived tumors were similar in mean size, implying that the phenotype is primarily expressed during initiation rather than in the promotion stage of carcinogenesis. Given these results, we surveyed a comprehensive mouse genome database and physically mapped Par2 within a 2.3 Mbp segment containing three known genes, Polı, Mbd2 and Dcc. Among those, the Polı seemed to be the most reasonable Par2 candidate, since it encodes an extremely error-prone DNA polymerase preferentially incorporating G or T opposite template T in vitro, reminiscent of the Kras2 activation because of an A to G or T point mutation within codon 61 with which most urethane-induced lung tumors are initiated. Indeed, our sequencing of Polı cDNAs from BALB/cByJ, C57BL/6J, A/J and C3H/ HeJ lungs revealed 21 BALB/cByJ-specific single-nucleotide polymorphisms in the coding region accompanied by seven amino-acid substitutions and an elevated frequency of alternative splicing, while no polymorphisms associated with tumor susceptibility were found for either Mbd2 or Dcc. Notably, we obtained evidence that BALB/cByJ Par2 alleles may selectively decrease the frequency of Kras2-mutated tumors compared with C57BL/6J alleles. Consequently, the Polı is an intriguing Par2 candidate clearly deserving further evaluation.

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Roles of the Pas1 and Par2 genes in determination of the unique, intermediate susceptibility of BALB/cByJ mice to urethane-induction of lung carcinogenesis: Differential effects on tumor multiplicity, size and Kras2 mutations

Cited by 21 publications

References 28 publications

Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia

Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia

Fine chromosomal localization of the mouse Par2 gene that confers resistance against urethane-induction of pulmonary adenomas

Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2 (Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner: detection of polymorphisms in the Polı gene as a candidate for Par2

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