This program represents a continuation of our efforts to understand, in molecular detail, how tumor viruses infect cells and how these viruses are associated with the conversion of a normal cell into a tumor cell. The six principal investigators engage in a conceptually and experimentally coherent approach to the understanding of how new viral information is inserted into the cell and ultimately into the chromosome; how once integrated into the chromosome, the expression of viral information may be responsible for a malignant phenotype, and finally, how cellular homologs of viral oncogenes may be altered to contribute to neoplastic changes. The proposal can be divided into four parts: 1) Mechanisms of Viral Entry: This problem centers largely on the identification of T4 as a specific receptor for AIDS virus and the ultimate construction of unique envelope structures on other viruses which may facilitate their targeting to specific cell types. 2) The Mechanisms by which Viral Genetic Information Integrates into the Chromosome: These studies attempt to provide a molecular mechanism for the integration, excision, and rearrangement of genetic information in both prokaryotes and eukaryotes. Moreover, experiments are described in which viral integration is exploited to isolate specific anti-oncogenes as well as to target genes to homologous loci in the chromosome at high frequency. 3) The Molecular Mechanism by which Known Human Papillomaviruses Transform Cervical Cells: These experiments examine the nature of the transcripts and the protein products in strains of human papillomavirus responsible for malignant transformation. 4) The Mechanisms by which Rearrangement of Cellular Oncogenes Result in Neoplastic Transformation: These studies attempt to identify new genes amplified in tumors and to understand the mechanism by which selective gene amplification contributes to the generation and maintenance of the neoplastic phenotype. This collaborative program provides a coherent approach to the understanding of how the introduction of new genetic information into the chromosome via viral infection and the rearrangement of pre-existing information into the chromosome may lead to malignant transformation, and how the information obtained in these studies can be used to study normal developmental processes.
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