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  • Oncogenomics
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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

Oncogene volume 22, pages 2374–2382 (2003)Cite this article

Abstract

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/cByJ↔BALB.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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Abbreviations

A:

A/J

B6:

C57BL/6J

C3H:

C3H/HeJ

Pas1 :

Pulmonary adenoma susceptibility 1

BALB:

BALB/cByJ

Par2 :

Pulmonary adenoma resistance 2

DEN:

diethylnitrosamine

PCR:

polymerase chain reaction

SNP:

single-nucleotide polymorphism

RT:

reverse transcription

β2-MG :

β2-microglobulin

References

  • Bebenek K, Tissier A, Frank EG, McDonald JP, Prasad R, Wilson SH, Woodgate R and Kunkel TA . (2001). Science, 291, 2156–2159.

  • Chen B, Johanson L, Wiest JS, Anderson MW and, You M . (1994). Proc. Natl. Acad. Sci. USA, 91, 1589–1593.

  • Cooper HM, Armes P, Britto J, Gad J and Wilks AF . (1995). Oncogene, 11, 2243–2254.

  • Devereux TR, Anna CH, Patel AC, White CM, Festing MFW and You M . (1997). Carcinogenesis, 18, 1751–1755.

  • Devereux TR, Wiseman RW, Kaplan N, Garren S, Foley JF, White CM, Anna C, Watson MA, Patel A, Jarchow S, Maronpot RR and Anderson MW . (1994). Mamm. Genome, 5, 749–755.

  • Dragani TA, Manenti G and Pierotti MA . (1995). Adv. Cancer Res., 67, 83–112.

  • Festing MFW, Yang A and Malkinson AM . (1994). Genet. Res., 64, 99–106.

  • Gariboldi M, Manenti G, Canzian F, Falvella FS, Radice MT, Pierotti MA, Della Porta G, Binelli G and Dragani TA . (1993). Nat. Genet., 3, 132–136.

  • Haracska L, Johnson RE, Unk I, Phillips BB, Hurwitz J, Prakash L and Prakash S . (2001). Proc. Natl. Acad. Sci. USA, 98, 14256–14261.

  • Hendrich B and Bird A . (1998). Mol. Cell. Biol., 18, 6538–6547.

  • Johnson RE, Washington MT, Haracska L, Prakash S and Prakash L . (2000). Nature, 406, 1015–1019.

  • Karasaki H, Obata M, Ogawa K and Lee G-H . (1997). Oncogene, 15, 1833–1840.

  • Lee G-H, Kawaguchi T, Nomura K and Kitagawa T . (1987). Hepatology, 7, 937–940.

  • Lee G-H, Matsushita H and Kitagawa T . (2001). Oncogene, 20, 3979–3985.

  • Lee G-H, Nomura K, Kanda H, Kusakabe M, Yoshiki A, Sakakura T and Kitagawa T . (1991). Cancer Res., 51, 3257–3260.

  • Malkinson AM and Beer DS . (1983). J. Natl. Cancer Inst., 70, 931–936.

  • Manam S, Storer RD, Prahalada S, Leander KR, Kraynak AR, Hammermeister CL, Joslyn DJ, Ledwith BJ, van Zwieten MJ, Bradley MO and Nichols WW . (1992). Mol. Carcinogen., 6, 68–75.

  • McDonald JP, Rapic-Otrin V, Epstain JA, Broughton BC, Wang X, Lehmann AR, Wolgemuth DJ and Woodgate R . (1999). Genomics, 60, 20–30.

  • Obata M, Nishimori H, Ogawa K and Lee G-H . (1996). Oncogene, 13, 1599–1604.

  • Tissier A, Frank EG, McDonald JP, Iwai S, Hanaoka F and Woodgate R . (2000a). EMBO J., 19, 5259–5266.

  • Tissier A, McDonald JP, Frank EG and Woodgate R . (2000b). Genes Dev., 14, 1642–1650.

  • You M, Wang Y, Stoner GD, Maronpot RR, Reynolds SH and Anderson MW . (1992). Proc. Natl. Acad. Sci. USA, 89, 5804–5808.

  • Zhang Y, Yuan F, Wu X, Taylor JS and Wang Z . (2001). Nucl. Acids Res., 29, 928–935.

  • Zhang Y, Yuan F, Wu X and Wang Z . (2000a). Mol. Cell Biol., 20, 7099–7108.

  • Zhang Z, Lin L, Liu G, Wang M, Hill J, Wang Y, You M and Devereux TR . (2000b). Exp. Lung Res., 26, 627–639.

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Acknowledgements

We thank Drs F Hanaoka and C Masutani for valuable discussion. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (G-HL, TT), the Ministry of Health, Welfare and Labor (G-HL) and the Okinaka Memorial Institute for Medical Research (G-HL), Japan.

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Authors and Affiliations

  1. Department of Pathology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Gang-Hong Lee & Hiroshi Matsushita

  2. Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, 060-8556, Japan

    Hiroyuki Nishimori, Yasushi Sasaki & Takashi Tokino

  3. Department of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, 170-8455, Japan

    Tomoyuki Kitagawa

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Correspondence to Gang-Hong Lee.

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Lee, GH., Nishimori, H., Sasaki, Y. et al. 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. Oncogene 22, 2374–2382 (2003). https://doi.org/10.1038/sj.onc.1206387

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