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The general aim of this application is to investigate the role of TAN-1 in leukemogenesis. TAN-1 is a homologue of the Drosophila Notch gene which controls cell fate in Drosophila embryogenesis. The protein contains specific motifs including ankyrin repeats, multiple EGF like repeats, etc. Another Drosophila gene, Delta, encodes a protein which binds to the TAN-1 EGF like repeats. The interaction between the two proteins controls cell fate in Drosophila, including neurogenesis. While the truncated overexpressed TAN-1 mutants localize in the nucleus this has not been shown for the mature protein in normal cells. Preliminary results suggest that the mature protein is proteolytically processed in normal cells in ways that result in generation of an independent intracellular domain. TAN-1 is often mutated in a subset of human acute T cell leukemias and lymphomas. Several domains exist in TAN-1 associated with its functions as a participator in signal transduction pathways. The role of these domains in leukemogenesis will be investigated by using a murine leukemia model in which the role of specific mutations in TAN-1 will be studied. These mutations will be induced by site directed mutagenesis. The proteins associated with TAN-1 will be identified by using tagged TAN-1 to screen for positive colonies in a lambda expression library. A complementary method will be also used to identify these proteins by co-precipitating TAN-1 associated proteins with anti- TAN-1 antibodies. Monoclonal antibodies are being raised against specific TAN-1 epitopes to be used for these studies.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.