The N-myc gene is frequently amplified and overexpressed in a highly restricted set of related human tumors, including neuroblastomas and retinoblastomas. We have demonstrated that the N-myc gene encodes a protein very related to that encoded by the classical c-myc protooncogene. Furthermore, we have also demonstrated that this gene may have a role both in tumorgenisis and in normal development. To further characterize this unique oncogene, we will isolate both from humans and from mice, the complete N-myc gene and its flanking regions as well as complete cDNA copies of the N-myc mRNA; these reagents will be used to determine the complete structure and nucleic acid sequence of the N-myc gene(s). Comparative analyses of the coding and non-coding regions of the human and murine N-myc genes with each other and with the related c-myc should help to eludidate important regulatory or functional regions. Our previous studies have demonstrated a remarkable tissue and developmental-stage specifically of N-myc expression. To characterize this phenomenon in more detail, we will study N-myc expression in developing rats and mice by cDNA/RNA in situ hybridization techniques. To determine the molecular elements involved in tissue or stage-specific N-myc expression, we will develop model cell culture systems with which to analyze regulation of N-myc expression by gene transfer technology. In addition, we will make N-myc-specific antisera which we will use to identify the N-myc protein and to localize it within the cell. Finally, we have derived considerable evidence which suggests that there is a family of myc-related genes, possibly specific for unique cell lineages or developmental stages. We have already isolated numerous members of the myc gene family, both from humans and from mice. We will characterize the structure of these and additional members of this family and assay for their function and expression as outlined above for the N-myc gene.
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