TY - JOUR
T1 - Additional evidence that the K-ras protooncogene is a candidate for the major mouse pulmonary adenoma susceptibility (Pas-1) gene
AU - Lin, Lin
AU - Festing, Michael F.W.
AU - Devereux, Theodora R.
AU - Crist, Keith A.
AU - Christiansen, Steven C.
AU - Wang, Yian
AU - Yang, Alice
AU - Svenson, Karen
AU - Paigen, Beverly
AU - Malkinson, Alvin M.
AU - You, Ming
N1 - Funding Information:
This work was supported by NIH grants CA58554 and ES02370. We thank Gary D. Stoner and Herman A. J. Schut for their critical reading of this manuscript. Address correspondence to Ming You, Department of Pathology, Medical College of Ohio, 3000 Arlington Avenue, Toledo, OH 43614, USA.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1998
Y1 - 1998
N2 - A locus for mouse pulmonary adenoma susceptibility, Pas-1, has been mapped on distal chromosome 6, where the K-ras gene is located. Allele- specific activation and expression of the K-ras allele from the susceptible parent has been observed in lung tumors from F1 hybrid mice. We report here genetic mapping of lung tumor susceptibility genes in urethane-treated A x B and B x A recombinant inbred (RI) mice using microsatellite markers to seek further evidence for the K-ras gent as candidate for Pas-1. The K-ras genotype differs between the A/J and C57BL/6J progenitors of the RI strains, and distal chromosome 6 contained a major lung tumor susceptibility determinant in the RI mice. Additional evidence that Pas-1 is K-ras involved linkage analysis of (A/J OLaHsd x BALB/cOLaHsd) F2 intercross mice whose parents shared the same K-ras genotype. In contrast to the results with the A x B and B x A RI strains, no distal chromosome 6 site was significantly associated with tumor development in these F2 mice. In addition to this major locus, linkage analysis of the RI mice revealed additional quantitative trait loci for susceptibility on chromosomes 10, 17, and 19. These loci may serve as modifiers of Pas-1. The relationship between the K-ras genotype and the frequency of K-ras mutations in urethane-induced lung tumors from the RI mice was also explored. All 18 tumor DNAs from RI mice with high susceptibility contained an A T → TA transversion at the second base of K-ras codon 61. This was also true for DNAs from 27 of 27 (100%) tumors in mice with high intermediate susceptibility. In RI strains with a low intermediate susceptibility, the DNA from 39 of 47 (83%) tumors contained an A T → TA transversion at condon 61, and only 13 of 21 (62%) tumors had this mutation in the most resistant group. This reflects a positive correlation between the frequency of K-ras mutations in lung tumors of A x B or B x A RI strains and their susceptibility to lung carcinogenesis. Since K-ras appears to be Pas- 1, these results suggest that some RI mice that have the resistant K-ras or Pas- 1 allele undergo tumor development by a K-ras-independent route.
AB - A locus for mouse pulmonary adenoma susceptibility, Pas-1, has been mapped on distal chromosome 6, where the K-ras gene is located. Allele- specific activation and expression of the K-ras allele from the susceptible parent has been observed in lung tumors from F1 hybrid mice. We report here genetic mapping of lung tumor susceptibility genes in urethane-treated A x B and B x A recombinant inbred (RI) mice using microsatellite markers to seek further evidence for the K-ras gent as candidate for Pas-1. The K-ras genotype differs between the A/J and C57BL/6J progenitors of the RI strains, and distal chromosome 6 contained a major lung tumor susceptibility determinant in the RI mice. Additional evidence that Pas-1 is K-ras involved linkage analysis of (A/J OLaHsd x BALB/cOLaHsd) F2 intercross mice whose parents shared the same K-ras genotype. In contrast to the results with the A x B and B x A RI strains, no distal chromosome 6 site was significantly associated with tumor development in these F2 mice. In addition to this major locus, linkage analysis of the RI mice revealed additional quantitative trait loci for susceptibility on chromosomes 10, 17, and 19. These loci may serve as modifiers of Pas-1. The relationship between the K-ras genotype and the frequency of K-ras mutations in urethane-induced lung tumors from the RI mice was also explored. All 18 tumor DNAs from RI mice with high susceptibility contained an A T → TA transversion at the second base of K-ras codon 61. This was also true for DNAs from 27 of 27 (100%) tumors in mice with high intermediate susceptibility. In RI strains with a low intermediate susceptibility, the DNA from 39 of 47 (83%) tumors contained an A T → TA transversion at condon 61, and only 13 of 21 (62%) tumors had this mutation in the most resistant group. This reflects a positive correlation between the frequency of K-ras mutations in lung tumors of A x B or B x A RI strains and their susceptibility to lung carcinogenesis. Since K-ras appears to be Pas- 1, these results suggest that some RI mice that have the resistant K-ras or Pas- 1 allele undergo tumor development by a K-ras-independent route.
KW - Genetic susceptibility
KW - K-ras
KW - Mouse lung
KW - Pas-1
KW - Recombinant inbred mice
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U2 - 10.3109/01902149809087382
DO - 10.3109/01902149809087382
M3 - Article
C2 - 9659579
AN - SCOPUS:14444278728
VL - 24
SP - 481
EP - 497
JO - Experimental Lung Research
JF - Experimental Lung Research
SN - 0190-2148
IS - 4
ER -