A person's risk of developing cancer depends on both genetic and environmental factors. To study the genetic predisposition to cancer without the influence of environmental variables, scientists study mice treated with urethane, a chemical carcinogen that induces lung tumors. By crossing inbred (genetically identical) strains of mice that are either resistant or susceptible to urethane-induced cancer, researchers can search for genes associated with tumor formation in the offspring. From previous work of this type using second-generation mice, it was already known that a region on chromosome 6 was associated with tumor formation. Now, a new study, carried out in a fourth-generation mouse population, focused to a single gene of chromosome 6 called Kras. This gene forms two different messenger RNA transcripts, called Kras-4A and Kras-4B, that produce two proteins with slightly different structure and, perhaps, function. The study found that mice susceptible to lung tumors have relatively more Kras-4A messenger RNA than resistant mice and that this difference may be due to small variations in the DNA near or within this gene.
Vyšlo v časopise: Mouse Pulmonary Adenoma Susceptibility 1 Locus Is an Expression QTL Modulating -4A. PLoS Genet 10(4): e32767. doi:10.1371/journal.pgen.1004307 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004307
1. GariboldiM, ManentiG, CanzianF, FalvellaFS, RadiceMT, et al. (1993) A major susceptibility locus to murine lung carcinogenesis maps on chromosome 6. Nature Genet 3 : 132–136.
2. ManentiG, DraganiTA (2005) Pas1 haplotype-dependent genetic predisposition to lung tumorigenesis in rodents: A meta-analysis. Carcinogenesis 26 : 875–882.
3. ManentiG, GalbiatiF, Giannì BarreraR, PettinicchioA, AcevedoA, et al. (2004) Haplotype sharing suggests that a genomic segment containing six genes accounts for the pulmonary adenoma susceptibility 1 (Pas1) locus activity in mice. Oncogene 23 : 4495–4504.
4. WangM, LemonWJ, LiuG, WangY, IraqiFA, et al. (2003) Fine mapping and identification of candidate pulmonary adenoma susceptibility 1 genes using advanced intercross lines. Cancer Res 63 : 3317–3324.
5. WangM, FutamuraM, WangY, YouM (2005) Pas1c1 is a candidate for the mouse pulmonary adenoma susceptibility 1 locus. Oncogene 24 : 1958–1963.
6. LiuP, WangY, VikisH, MaciagA, WangD, et al. (2006) Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice. Nat Genet 38 : 888–895.
7. KingPD, LubeckBA, LapinskiPE (2013) Nonredundant functions for ras GTPase-activating proteins in tissue homeostasis. Sci Signal 6: re1.
8. YouM, CandrianU, MaronpotRR, StonerGD, AndersonMW (1989) Activation of the ki-ras protooncogene in spontaneously occurring and chemically induced lung tumors of the strain A mouse. Proc Natl Acad Sci USA 86 : 3070–3074.
9. ReFC, ManentiG, BorrelloMG, ColomboMP, FisherJH, et al. (1992) Multiple molecular alterations in mouse lung tumors. Mol Carcinog 5 : 155–160.
10. JohnsonL, MercerK, GreenbaumD, BronsonRT, CrowleyD, et al. (2001) Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410 : 1111–1116.
11. MeuwissenR, LinnSC, van dV, MooiWJ, BernsA (2001) Mouse model for lung tumorigenesis through cre/lox controlled sporadic activation of the K-ras oncogene. Oncogene 20 : 6551–6558.
12. ZhangZ, WangY, VikisHG, JohnsonL, LiuG, et al. (2001) Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat Genet 29 : 25–33.
13. ToMD, Perez-LosadaJ, MaoJH, HsuJ, JacksT, et al. (2006) A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. Nat Genet 38 : 926–930.
14. PriorIA, HancockJF (2012) Ras trafficking, localization and compartmentalized signalling. Semin Cell Dev Biol 23 : 145–153.
15. VoiceJK, KlemkeRL, LeA, JacksonJH (1999) Four human ras homologs differ in their abilities to activate raf-1, induce transformation, and stimulate cell motility. J Biol Chem 274 : 17164–17170.
16. PlowmanSJ, ArendsMJ, BrownsteinDG, LuoF, DevenneyPS, et al. (2006) The K-ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice. Exp Cell Res 312 : 16–26.
17. WangY, YouM, WangY (2001) Alternative splicing of the K-ras gene in mouse tissues and cell lines. Exp Lung Res 27 : 255–267.
18. PellsS, DivjakM, RomanowskiP, ImpeyH, HawkinsNJ, et al. (1997) Developmentally-regulated expression of murine K-ras isoforms. Oncogene 15 : 1781–1786.
19. ToMD, WongCE, KarnezisAN, Del RosarioR, Di LauroR, et al. (2008) Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nat Genet 40 : 1240–1244.
20. PatekCE, ArendsMJ, WallaceWA, LuoF, HaganS, et al. (2008) Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis. Exp Cell Res 314 : 1105–1114.
21. ChenB, JohansonL, WiestJS, AndersonMW, YouM (1994) The second intron of the K-ras gene contains regulatory elements associated with mouse lung tumor susceptibility. Proc Natl Acad Sci USA 91 : 1589–1593.
22. DarvasiA, SollerM (1995) Advanced intercross lines, an experimental population for fine genetic mapping. Genetics 141 : 1199–1207.
23. BonnerAE, LemonWJ, DevereuxTR, LubetRA, YouM (2004) Molecular profiling of mouse lung tumors: Association with tumor progression, lung development, and human lung adenocarcinomas. Oncogene 23 : 1166–1176.
24. MelkamuT, ZhangX, TanJ, ZengY, KassieF (2010) Alteration of microRNA expression in vinyl carbamate-induced mouse lung tumors and modulation by the chemopreventive agent indole-3-carbinol. Carcinogenesis 31 : 252–258.
25. Jones-BolinSE, JohanssonE, PalmisanoWA, AndersonMW, WiestJS, et al. (1998) Effect of promoter and intron 2 polymorphisms on murine lung K-ras gene expression. Carcinogenesis 19 : 1503–1508.
26. TimofeevaOA, GorshkovaEV, LevashovaZB, KobzevVF, FilipenkoML, et al. (2002) Pulmonary carcinogenesis susceptibility-associated single-nucleotide polymorphisms in K-ras intron 2 affect the binding of factor gata-6 but not gene expression. Mol Biol (Mosk) 36 : 817–824.
27. ShimkinMB, StonerGD (1975) Lung tumors in mice: Application to carcinogenesis bioassay. Adv Cancer Res 21 : 1–58.
28. BromanKW, WuH, SenS, ChurchillGA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19 : 889–890.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
