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Gene Review

Par2  -  pulmonary adenoma resistance 2

Mus musculus

 
 
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Disease relevance of Par2

 

High impact information on Par2

  • Par2 and Par4, however, do not affect lung tumor size, which is instead controlled by an additional locus that we have mapped on the central region of chromosome 4 [3].
  • Consequently, the Poli is an intriguing Par2 candidate clearly deserving further evaluation [4].
  • Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous [4].
  • Among those, the Poli 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 [4].
  • By comparing the deduced Par2 genotype of each recombinant with its recombinational breakpoint, the Par2 locus was confined to an approximately 0.5 cM region flanked by D18Mit103 and D18Mit188 loci [1].
 

Biological context of Par2

  • 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 [4].
  • The Par2 genotype exhibited no effect on this parameter [5].
  • The BALB Par2 allele only significantly reduced the mean lung tumor multiplicity (LOD = 4.4) in the backcross population carrying the BALB allele of Pas1, indicating that the intermediate BALB phenotype may at least in part be the result of interactions between these two dominant genes [5].
  • We recently found that BALB mice possess a unique lung tumor resistance gene on chromosome 18, designated Par2 (Pulmonary adenoma resistance 2), which partially, but dominantly suppresses the sensitive phenotype of A/J mice (Oncogene 13: 1599-1604, 1996) [5].
  • By stable transfection with either an empty vector (DM5/EV) or an expression vector encoding mouse PAR-2 cDNA (DM5/Par2), a pair of lung fibroblast cell lines with or without functional PAR-2 expression were prepared [6].
 

Other interactions of Par2

  • While the BALB Pas1 allele increased both the mean multiplicity and size of lung tumors, the BALB Par2 allele affected only the mean tumor multiplicity, implying that they are involved in different stages of multi-step lung carcinogenesis [5].
  • Previously, we excluded Smad4 and Smad2 as candidates for Par2 based on the lack of functional polymorphism(s) and differential expression in lungs from A/J and BALB/c mice [7].
  • Identification of the Par2 (Pulmonary adenoma resistance) locus on mouse chromosome 18, a major genetic determinant for lung carcinogen resistance in BALB/cByJ mice [8].
  • In a number of recent studies, a lung tumor resistance locus designated either Par2 or Pas7 was mapped to distal chromosome 18 in crosses between susceptible A/J and more resistant BALB/c mice [7].

References

  1. Fine chromosomal localization of the mouse Par2 gene that confers resistance against urethane-induction of pulmonary adenomas. Lee, G.H., Matsushita, H., Kitagawa, T. Oncogene (2001) [Pubmed]
  2. Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk. Sakiyama, T., Kohno, T., Mimaki, S., Ohta, T., Yanagitani, N., Sobue, T., Kunitoh, H., Saito, R., Shimizu, K., Hirama, C., Kimura, J., Maeno, G., Hirose, H., Eguchi, T., Saito, D., Ohki, M., Yokota, J. Int. J. Cancer (2005) [Pubmed]
  3. Genetic mapping of lung cancer modifier loci specifically affecting tumor initiation and progression. Manenti, G., Gariboldi, M., Fiorino, A., Zanesi, N., Pierotti, M.A., Dragani, T.A. Cancer Res. (1997) [Pubmed]
  4. 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 Poli gene as a candidate for Par2. Lee, G.H., Nishimori, H., Sasaki, Y., Matsushita, H., Kitagawa, T., Tokino, T. Oncogene (2003) [Pubmed]
  5. 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. Karasaki, H., Obata, M., Ogawa, K., Lee, G.H. Oncogene (1997) [Pubmed]
  6. Cockroach allergen extract stimulates protease-activated receptor-2 (PAR-2) expressed in mouse lung fibroblast. Kondo, S., Helin, H., Shichijo, M., Bacon, K.B. Inflamm. Res. (2004) [Pubmed]
  7. Fine mapping and characterization of candidate lung tumor resistance genes for the Par2 locus on mouse chromosome 18. Zhang, Z., Lin, L., Liu, G., Wang, M., Hill, J., Wang, Y., You, M., Devereux, T.R. Exp. Lung Res. (2000) [Pubmed]
  8. Identification of the Par2 (Pulmonary adenoma resistance) locus on mouse chromosome 18, a major genetic determinant for lung carcinogen resistance in BALB/cByJ mice. Obata, M., Nishimori, H., Ogawa, K., Lee, G.H. Oncogene (1996) [Pubmed]
 
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