Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice

We have used large-scale insertional mutagenesis to identify functional landmarks relevant to cancer in the recently completed mouse genome sequence. We infected Cdkn2a −/− mice with Moloney murine leukemia virus (MoMuLV) to screen for loci that can participate in tumorigenesis in collaboration with...

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Vydané v:	Nature genetics Ročník 32; číslo 1; s. 160 - 165
Hlavní autori:	Lund, Anders H., Turner, Geoffrey, Trubetskoy, Alla, Verhoeven, Els, Wientjens, Ellen, Hulsman, Danielle, Russell, Robert, DePinho, Ronald A., Lenz, Jack, van Lohuizen, Maarten
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.09.2002 Nature Publishing Group
Predmet:	Agriculture Animal Genetics and Genomics Animals Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Cancer Research Cell Transformation, Neoplastic Cells, Cultured Chromosome Mapping Classical genetics, quantitative genetics, hybrids Collaboration Complications and side effects Cyclin-Dependent Kinase Inhibitor p16 - deficiency Cyclin-Dependent Kinase Inhibitor p16 - genetics Diagnosis Fundamental and applied biological sciences. Psychology Gene expression Gene Function Gene loci Gene mutations Genetic aspects Genetics Genetics of eukaryotes. Biological and molecular evolution Genome Genomes Genomics Health aspects Human Genetics Humans Infections Kinases letter Leukemia Lymphoma Lymphoma - genetics Mice Molecular Sequence Data Moloney murine leukemia virus Moloney murine leukemia virus - genetics Mutagenesis Mutagenesis, Insertional Neoplasms - genetics Proviruses - genetics Retrovirus Risk factors Sarcoma Spleen Tumorigenesis Tumors Vertebrata Netherlands United States > US Vertebrata Mammalia Gene Mouse Rodentia Tagging Malignant tumor Genome
ISSN:	1061-4036, 1546-1718
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Shrnutí:	We have used large-scale insertional mutagenesis to identify functional landmarks relevant to cancer in the recently completed mouse genome sequence. We infected Cdkn2a −/− mice with Moloney murine leukemia virus (MoMuLV) to screen for loci that can participate in tumorigenesis in collaboration with loss of the Cdkn2a -encoded tumor suppressors p16INK4a and p19ARF. Insertional mutagenesis by the latent retrovirus was synergistic with loss of Cdkn2a expression, as indicated by a marked acceleration in the development of both myeloid and lymphoid tumors. We isolated 747 unique sequences flanking retroviral integration sites and mapped them against the mouse genome sequence databases from Celera and Ensembl. In addition to 17 insertions targeting gene loci known to be cancer-related, we identified a total of 37 new common insertion sites (CISs), of which 8 encode components of signaling pathways that are involved in cancer. The effectiveness of large-scale insertional mutagenesis in a sensitized genetic background is demonstrated by the preference for activation of MAP kinase signaling, collaborating with Cdkn2a loss in generating the lymphoid and myeloid tumors. Collectively, our results show that large-scale retroviral insertional mutagenesis in genetically predisposed mice is useful both as a system for identifying genes underlying cancer and as a genetic framework for the assignment of such genes to specific oncogenic pathways.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	1061-4036 1546-1718
DOI:	10.1038/ng956