The goal of this program project application is to investigate the connection between disrupted development and cancer. We will use an integrated multi-organismal approach, with a specific focus on transcription factors that regulate normal development and that have also been implicated in oncogenesis. A large body of research has now shown that the genes that cause cancer appear to operate by four general mechanisms: (1) aberrant signal transduction resulting in inappropriate cell growth (oncogenes such as sis, erbB, src, ras, NF-1, raf, jun, fos, and myc); (2) failure of cell cycle arrest and programmed cell death pathways (bcl2, p53, Rb, p16); (3) aberrant DNA repair (mutS and mutL homologs); and (4) misregulation of transcription factors which appear to regulate cell identity during differentiation (HOX, HRX, PBX, bmi-1, myb, maf). The latter mechanism is poorly understood at present and is the focus of this proposal. Because many of the transcription factors which regulate development and also cause cancer have been highly conserved during evolution, there is an opportunity to take advantage of the complementary strengths of several experimental-systems and investigators in order to unravel the relationship between inappropriate determination of cell identity and oncogenesis. We therefore propose to study several such gene families in parallel using a vertically integrated approach which will employ: the "knock-out" genetics and human-relatedness of the laboratory mouse; the genetic toolbox and extensive knowledge of development, cell cycle regulation, and cytogenetics in Drosophila melanogaster; and the nearly complete knowledge of the cell lineage, genetic map, and physical genome map of Caenorhabditis elegans.