Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging.
Murine retroviruses may cause malignant tumors in mice by insertional mutagenesis of host genes. The use of retroviral tagging as a means of identifying cancer-causing genes has, however, almost entirely been restricted to hematopoietic tumors. The aim of this study was to develop a system allowing for the retroviral tagging of candidate genes in malignant brain tumors. Mouse gliomas were induced by a recombinant Moloney murine leukemia virus encoding platelet-derived growth factor (PDGF) B-chain. The underlying idea was that tumors evolve through a combination of PDGF-mediated autocrine growth stimulation and insertional mutagenesis of genes that cooperate with PDGF in gliomagenesis. Common insertion sites (loci that were tagged in more than one tumor) were identified by cloning and sequencing retroviral flanking segments, followed by blast searches of mouse genome databases. A number of candidate brain tumor loci (Btls) were identified. Several of these Btls correspond to known tumor-causing genes; these findings strongly support the underlying idea of our experimental approach. Other Btls harbor genes with a hitherto unproven role in transformation or oncogenesis. Our findings indicate that retroviral tagging with a growth factor-encoding virus may be a powerful means of identifying candidate tumor-causing genes in nonhematopoietic tumors.
Department of Genetics and Pathology, The Rudbeck Laboratory, University Hospital, SE-751 85 Uppsala, Sweden.
Fredrik K
FK
Johansson
Josefin
J
Brodd
Charlotta
C
Eklöf
Maria
M
Ferletta
Göran
G
Hesselager
Carl-Fredrik
CF
Tiger
Lene
L
Uhrbom
Bengt
B
Westermark
D000818:Animals; D000831:Animals, Newborn; D001932:Brain Neoplasms / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008979:Moloney murine leukemia virus / Q000235:genetics*; D016254:Mutagenesis, Insertional; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics*; D015398:Signal Transduction
D020574:Proto-Oncogene Proteins c-sis