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...

A few general transcription factors, in particular TFIID and TFIIB, have been found to bind transcriptional activators. Here we show that the general transcription factor TFIIF is also a target for a transcriptional activator, namely serum response factor (SRF), which binds to the c-fos promoter. Using a yeast interaction assay, we find that SRF binds the RAP74 subunit of TFIIF and that SRF's transcriptional activation domain is the region involved in this binding. Further, RAP74's central charged cluster domain is required for binding to SRF's activation domain. Deletion of this domain impairs RAP74's ability to support SRF-activated transcription in vitro but has little effect on the protein's basal transcription activity or its ability to support SP1-activated transcription. The correlation of SRF-RAP74 binding with transcriptional activation suggests that RAP74 is a critical target for SRF-activated transcription.

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