Histological and anatomopathological studies performed on 152 independent myeloblastosis-associated virus type 1 (MAV1)-induced nephroblastomas allowed us to precisely define the chronology of tumor development in chickens. Three tumors representing increasing developmental stages were used to construct genomic libraries and to study both the state of proviral genomes and the sites of MAV1 integration in genomic DNA. We established that increasing levels of proviral rearrangement, eventually leading to the elimination of infectious MAV genomes, were associated with tumor progression and that 22 individual tumors, representative of different developmental stages, did not contain any common MAV1 integration site. Cloning of cellular fragments flanking the MAV1-related proviruses in tumor DNA showed that each one of eight nephroblastomas tested expressed a high level of an as yet unidentified cellular gene (nov) whose transcription is normally arrested in adult kidney cells. Cloning of the normal nov gene established that in one tumor, fused long terminal repeat-truncated nov mRNA species were expressed, indicating that at least in that case, the high level of nov expression was under the control of the MAV long terminal repeat promoter. The normal nov gene encodes a putative 32-kDa secreted polypeptide, which is a member of a new family of proteins likely to be involved in cell growth regulation. We also showed that the expression of an amino-terminal-truncated nov product in chicken embryo fibroblasts was sufficient to induce their transformation.The avian nephroblastoma induced by myeloblastosisassociated virus (MAV) is generally considered a good model for the human Wilms' tumor because of their histological similarities (i.e., embryonic tissues consisting of a heterogeneous mixture of immature and differentiated renal elements) (18,23). It is now well established that nephroblastoma development in humans is associated with deletion of at least one of two distinct genetic loci assigned to chromosome 11: llpl3 (11,27,33,40), lip15 (26,37), and alteration of a locus outside of llp (16,21,43). There is also a growing body of evidence to suggest that recessive alleles at these loci are involved in tumorigenesis. Recently, one of the candidate Wilms' tumor genes, located at the chromosome llpl3 locus within the WAGR complex, was reported to encode a potential zinc finger protein (7,13).We believe that studying MAV-induced nephroblastoma may lead to the characterization of molecular events associated with tumor development which might not be directly accessible in the human system. MAV is a replicationcompetent retrovirus responsible for the induction of nephroblastoma, osteogenic osteoblastoma (osteopetrosis), and, less frequently, lymphoid leukemia and sarcoma in chickens (48). On the basis of differences in their pathogenicity, two strains of MAV2 were identified as inducing preferentially osteopetrosis [MAV2 (0) for these two viral strains confirmed that they were genetically distinct (54), but the molecular basi...
Histological and anatomopathological studies performed on 152 independent myeloblastosis-associated virus type 1 (MAV1)-induced nephroblastomas allowed us to precisely define the chronology of tumor development in chickens. Three tumors representing increasing developmental stages were used to construct genomic libraries and to study both the state of proviral genomes and the sites of MAV1 integration in genomic DNA. We established that increasing levels of proviral rearrangement, eventually leading to the elimination of infectious MAV genomes, were associated with tumor progression and that 22 individual tumors, representative of different developmental stages, did not contain any common MAV1 integration site. Cloning of cellular fragments flanking the MAV1-related proviruses in tumor DNA showed that each one of eight nephroblastomas tested expressed a high level of an as yet unidentified cellular gene (nov) whose transcription is normally arrested in adult kidney cells. Cloning of the normal nov gene established that in one tumor, fused long terminal repeat-truncated nov mRNA species were expressed, indicating that at least in that case, the high level of nov expression was under the control of the MAV long terminal repeat promoter. The normal nov gene encodes a putative 32-kDa secreted polypeptide, which is a member of a new family of proteins likely to be involved in cell growth regulation. We also showed that the expression of an amino-terminal-truncated nov product in chicken embryo fibroblasts was sufficient to induce their transformation.
We have previously reported that expression of the c-myb gene in normal avian thymic cells proceeds through the intermolecular recombination of ET (thymusspecific) and c-myb coding sequences, thereby generating a novel type of c-myb product. Antisense transcripts expressed from the ET locus encode the extremely well-conserved splicing factor PR264/SC35. We now show that the human PR264 promoter sequences contain several myb-recognition elements that efficiently interact in vito with the c-myb DNA-binding domain. Moreover, expression from the PR264 promoter is transactivated, both in vitro and in cultured cells, by different c-myb products. Thus, the PR264 gene is most likely a physiological target for the c-myb family of transcription factors.
Chicken embryo fibroblasts sensitized by ts RSV respond to TGFs present in the media of non-transformed FR3T3 and NRK-4 rat cells and of the same cells transformed by KiMSV or RSV. They also respond to TGFs present in the media of BHK hamster cells transformed by MoMSV, PyV or RSV. Two other indicator rat cell lines, untransformed NRK-4 and FR3T3, sensitized by ts KiMSV, respond to the same TGF-containing media, and this response is increased by exogenous EGF. Normal FR3T3 cells failed to respond to any of the media. The most sensitive target cells were the ts KiMSV-FR3T3 cells at the restrictive temperature (39.5 degrees C). All the media tested on NRK-49F target cells required EGF for their TGF activity which was essentially dependent on prior activation by acidification. These data show that the above media from non-transformed or transformed cells contain beta-TGFs, with no detectable accompanying alpha-TGF activity. The release of and the response to these TGFs are not interdependent. A function of ts mutant src and k-ras viral oncogenes, still expressed at the restrictive temperature, can sensitize non-responsive cells, without there being any specificity towards the TGF producer cells.
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