A Function of Fas-Associated Death Domain Protein in Cell Cycle Progression Localized to a Single Amino Acid at Its C-Terminal Region

Abstract

FADD is an adaptor known to transmit apoptotic signals from members of the tumor necrosis factor receptor family. We show here that FADD has a domain implicated in cell proliferation. Mice bearing the Asp mutation in the serine 191 phosphorylation site are runted and anemic and display splenomegaly. Apoptosis is unimpaired in these mice, but they exhibit many immune developmental problems indicative of proliferative defects. Mutant FADD T cells are defective in cell cycle progression, suggesting that regulation of phosphorylation at serine 191 is essential for growth/proliferation. Remarkably, serine 191 is conserved among mammalian FADD proteins, but this C-terminal region is absent in lower organisms, suggesting that FADD acquired a domain during evolution, rendering it a "proliferation-apoptosis coupler" that balances cell proliferation and apoptosis.

Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes

“…Indeed, it has been shown recently that a specific mutation in FADD impedes cell proliferation but has no effect on its ability to transduce a death signal from Fas. 49 The mobility shift that we found provides the first physical evidence that FADD is specifically modified after mitogenic stimulation. Our finding that caspase-8 is recruited to larger complexes after mitogenic stimulation, and not only after 'death receptor' ligation, strengthens the evidence that caspase-8 plays an essential role in T-cell-mediated immune responses.…”

c-FLICE inhibitory protein expression inhibits T-cell activation

“…In addition, we observed suppressed proliferation of T cells in all transgenic mice ( Figure 5). Defective proliferation is found in T cells from FADD-deficient chimeric mice and dominant-negative FADD-transgenic mice, [13][14][15][16][17][18][19][20] and in T cells with inactivated caspase-8. [21][22][23][24][25] Overexpression of c-FLIP, therefore, results in T-cell proliferation defects similar to those with FADD and caspase-8 inactivation.…”

“…[13][14][15][16][17][18][19][20][21][22][23][24][25] IL-2 production, another major T-cell activation indicator, was analyzed in c-FLIP-transgenic T cells stimulated by ant-CD3. IL-2 production from FLIP-transgenic thymocytes was consistently lower than NLC thymocytes (Figure 5d).…”

“…12 T cells from FADD-deficient chimeric mice and dominant-negative FADD-transgenic mice display profound inhibition of proliferation. [13][14][15][16][17][18][19][20] T-cell activation is reported to stimulate caspase-8 and suppression of caspase-8 prevents T-cell activation. 21,22 More recently, caspase-8 mutation in human and mouse was linked to defective lymphocyte activation and immunodeficiency.…”

Body language: the function of PML nuclear bodies in apoptosis regulation

“…Unexpectedly, FADD was recently found to localise preferentially to the nucleus in different adherent cell lines 96 and, additionally, murine FADD was demonstrated to be essential for regulating cell proliferation and cell cycle progression in lymphocytes. 97 The latter function depends on its specific phosphorylation at serine, 191, 97 a conserved site equivalent to serine 194 in human FADD. 98 FADD-deficient mice die in utero, suggesting that FADD also plays a role in nonlymphoid tissue proliferation.…”