The long-range goals of the program Project are to elucidate and characterize basic mechanisms that regulate growth related and developmentally related genes as they are normally expressed or inappropriately expressed in neoplastic cells. Substantial progress towards these goals has been achieved with the Program Project in years 01- 04. Cancer may be characterized by the dysregulated growth of cells which phenotypically fail to recapitulate normal differentiation and development; it may also result from a failure of programmed (apoptotic) cell death. This Program Project proposes to analyze the normal and abnormal regulation of growth and development through analyses of different but highly related genetically regulated pathways, through analysis of the sequences and interactive proteins that regulate essential genes within these pathways, and through analysis of loss and gain of function of these genes in mice and embryonic stem (ES) cells. The strategy is common to each of the projects and extends from an in-depth analysis of the regulation of transcription of these genes and the factors that mediate this regulation, the identification and characterization of DNA elements that mediate tissue and developmental stage specific expression, to the use of these genes and regulatory elements to modify lineage and temporal specific expression of growth and development by introduction of them in cells, transgenic mice, and loss of function mice through targeted disruption of these genes. It is hoped to test the hypothesis that understanding these normal and abnormal regulatory mechanisms will lead to logical approaches for the treatment of neoplastic disease in man. We will focus on growth factor genes, genes that appear to direct differentiation functions, genes that function to prevent cell death (apoptosis), genes that encode transcription factors that are activated by growth factors and that direct nuclear signals to program growth factor signals, and highly developmentally regulated genes that are expressed in a lineage specific manner. The tools of molecular biology, cell biology, biochemistry, and immunology will be used. cDNA and genomic cloning, DNA sequencing, identification of cis- acting elements, identification and purification of transacting transcriptional proteins, transcriptional analyses, in situ hybridization and immunoperoxidase analyses, both gain of function and loss of function experiments in the transgenic mouse and in heterozygous and homozygously targeted loss of function mice are planned. Common themes of research interests and goals, technologies, and reagents exist to advance the progress of the Program Project. Core programs with an interactive program of informal and formal meetings will facilitate research and the generation of new ideas and thus to advance the goals of the Program Project. Informal and formal review will ensure orderly and optimum advancement of the research goals. The collective goals, themes, and interactive programs ensure progress to a level that is not achievable without the context of a program project.
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