A dominant negative Fas-associated death domain protein mutant inhibits proliferation and leads to impaired calcium mobilization in both T-cells and fibroblasts

Death domain-containing members of the tumor necrosis factor (TNF) receptor family ("death receptors") can induce apoptosis upon stimulation by their naural ligands or by agonistic antibodies. Activated death receptors recruit death domain adapter proteins like Fas-associated death domain protein (FADD), and this ultimately leads to proteolytic activation of the caspase cascade and cell death. Recently, FADD has also been implicated in the regulation of proliferation; functional inhibition of FADD results in p53-dependent impairment of proliferation in activated T-cells. In this study we have further analyzed T-cells derived from transgenic mice expressing a dominant negative FADD mutant (FADD DN) under control of lck promoter in vitro so as to identify the signaling pathways that become engaged upon T-cell receptor stimulation and that are regulated by death receptors. FADD DN expression inhibits T-cell proliferation, both at the G(0)-S transition and in the G(1) phase of continuously proliferating cells.