The long term goal of this proposed research is to understand the mechanisms of apoptosis in malignant and primary T cells. Fas is a member of the tumor necrosis factor receptor superfamily and is expressed on activated T cells and many malignant cells. Treatment with anti-Fas antibody leads to apoptosis in many but not all the tumor cells. A similar situation can also be found for T cells from different developmental stages. Immature T cells is particularly susceptible to Fas-induced apoptosis while mature T cells are quite resistant to the apoptotic-effect of anti-Fas antibodies. Mort 1 /FADD is a protein with a death domain, a protein-protein interaction domain that is also found in the cytoplasmic tail of Fas and tumor necrosis factor receptor p55. In sensitive cells, addition of anti-Fas antibodies triggers Mort1 to associate with Fas. Interference of this association process by a dominant negative Mort1 protein leads to inhibition of apoptosis. In several malignant cell lines that are resistant to Fas-mediated apoptosis, Mortl was found not to associate with Fas. Thus, Mortl-Fas association is a key step in Fas-induced apoptosis that might determine susceptibility of a cell to anti-Fas-mediated cell death. Lymphomas, thymomas and T cell hybridomas as well as transgenic and gene-targeted mutant mice will be used to understand the role of Mortl in apoptosis of malignant and primary T cells. The following specific aims are proposed. First, structure-function analysis of the Mortl protein will be performed using a Fas/Mortl chimeric protein. Second, the molecular process of Mortl/Fas association will be examined in malignant and primary T cells. Third, Mortl-deficient mice will be generated and analyzed. Fourth, the role of Mort I and one of its associating protein in apoptosis of immature T cells will be examined. The above aims should lead to a better understanding of the mechanisms of peripheral and central tolerance and why some tumor cells are resistant to Fas-induced apoptosis. The information obtained might lead to means by which apoptosis in resistant tumor cells might be induced and to halting of the onset of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Experimental Immunology Study Section (EI)
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Mccarthy, Susan A
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University of California Berkeley
Schools of Arts and Sciences
United States
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