This proposal has 5 parts representing 5 on-going efforts by different groups of junior investigators in the laboratory. They are: 1. Conditional Abl knockout. Having knocked out both the Abl and Arg genes and found that one of the two genes is needed for development beyond embryonic day 10, we plan to construct a conditional knockout of Abl on an Arg-deficient background so that the roles of the genes in later stages of mouse development and function can be examined. 2. Abl in C. elegans. Abl function has been investigated in mice and Drosophila but the putative functions of the gene are so variable that examination of another organism is warranted. We have chosen C. elegans because its entire genome is known and it is possible to examine it genetically at very high resolution. 3. NF-kappaB control of transcription. While there is much fragmentary knowledge of the genes controlled by NF-kappaB, a global analysis of gene expression in cells with defined genetic lesions in the NF-kappaB-related proteins will give more precise knowledge of which genes are controlled and by which subunits. 4. NF-kappaB activation by TANK and TBK1. There are numerous pathways of NF-kappaB activation but none are known in precise detail. We have found a new kinase, TBK1, that interacts with TANK and appears to act along with TRAF proteins and may phosphorylate them. A deeper knowledge of the details of the biochemistry of these events could help to understand the precise mechanisms of NFkappaB activation. 5. ATR kinase. This very large kinase has been implicated in checkpoint control of the cell cycle in mammalian cells. We have knocked out the gene for this protein and the mice die very early in gestation, in a manner similar to mice lacking the BRCA genes. We plan to construct a conditional allele of this gene to examine in more detail its function and, in particular, its relation to p53, BRCA1 and 2, and Chk1. These studies are all aimed at a deeper understanding of both the processes of oncogenic transformation and the normal development and function of mammals.
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