Integration of Myeloblastosis Associated Virus proviral sequences occurs in the vicinity of genes encoding signaling proteins and regulators of cell proliferation
- Equal contributors
1 Laboratoire d'Oncologie Virale et Moléculaire, Case 7048, UFR de Biochimie, 2 place Jussieu, Université Paris 7 D. Diderot, 75005 Paris, France
2 Laboratoire de Cytogénétique and CNRS UMR 8125, Institut Gustave Roussy, 94805 Villejuif, France
3 Unite de Génétique Moléculaire et de Biologie du Développement (CNRS UPR 420), 94801 Villejuif, France
4 Endocrinologie et génétique du développement et de la reproduction INSERM U 782 92140 Clamart (France)
5 Cellular regulations and oncogenesis-UMR 146 CNRS/Institut Curie
6 Genexpress, Functional Genomics and Systems Biology for Health, CNRS UMR 7091-7, 94801 Villejuif Cedex, France
7 UPR 1983, CNRS, 7 rue Guy Moquet, 94801, Villejuif Cedex, France
Cell Communication and Signaling 2006, 4:1 doi:10.1186/1478-811X-4-1Published: 10 January 2006
Myeloblastosis Associated Virus type 1 (N) [MAV 1(N)] induces specifically nephroblastomas in 8–10 weeks when injected to newborn chicken. The MAV-induced nephroblastomas constitute a unique animal model of the pediatric Wilms' tumor. We have made use of three independent nephroblastomas that represent increasing tumor grades, to identify the host DNA regions in which MAV proviral sequences were integrated. METHODS Cellular sequences localized next to MAV-integration sites in the tumor DNAs were used to screen a Bacterial Artificial Chromosomes (BACs) library and isolate BACs containing about 150 kilobases of normal DNA corresponding to MAV integration regions (MIRs). These BACs were mapped on the chicken chromosomes by Fluorescent In Situ Hybridization (FISH) and used for molecular studies.
The different MAV integration sites that were conserved after tumor cell selection identify genes involved in the control of cell signaling and proliferation. Syntenic fragments in human DNA contain genes whose products have been involved in normal and pathological kidney development, and several oncogenes responsible for tumorigenesis in human.
The identification of putative target genes for MAV provides important clues for the understanding of the MAV pathogenic potential. These studies identified ADAMTS1 as a gene upregulated in MAV-induced nephroblastoma and established that ccn3/nov is not a preferential site of integration for MAV as previously thought. The present results support our hypothesis that the highly efficient and specific MAV-induced tumorigenesis results from the alteration of multiple target genes in differentiating blastemal cells, some of which are required for the progression to highly aggressive stages. This study reinforces our previous conclusions that the MAV-induced nephroblastoma constitutes an excellent model in which to characterize new potential oncogenes and tumor suppressors involved in the establishment and maintenance of tumors.