Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1

Abstract

Programmed cell death, or apoptosis, is important in homeostasis of the immune system: for example, non-functional or autoreactive lymphocytes are eliminated through apoptosis. One member of the tumour necrosis factor receptor (TNFR) family, Fas (also known as CD95 or Apo-1), can trigger cell death and is essential for lymphocyte homeostasis. FADD/Mort1 is a Fas-associated protein that is thought to mediate apoptosis by recruiting the protease caspase-8. A dominant-negative mutant of FADD inhibits apoptosis initiated by Fas and other TNFR family members. Other proteins, notably Daxx, also bind Fas and presumably mediate a FADD-independent apoptotic pathway. Here we investigate the role of FADD in vivo by generating FADD-deficient mice. As homozygous mice die in utero, we generated FADD-/- embryonic stem cells and FADD-/- chimaeras in a background devoid of the recombination activating gene RAG-1, which activates rearrangement of the immunoglobulin and T-cell receptor genes. We found that thymocyte subpopulations were apparently normal in newborn chimaeras. Fas-induced apoptosis was completely blocked, indicating that there are no redundant Fas apoptotic pathways. As these mice age, their thymocytes decrease to an undetectable level, although peripheral T cells are present in all older FADD-/- chimaeras. Unexpectedly, activation-induced proliferation is impaired in these FADD-/- T cells, despite production of the cytokine interleukin (IL)-2. These results and the similarities between FADD-/- mice and mice lacking the beta-subunit of the IL-2 receptor suggest that there is an unexpected connection between cell proliferation and apoptosis.

Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1)

“…In support of this idea, it is well known that Bid is required in only a subset of cell types and in cell death caused by a certain subset of stimuli. 40 The fact that apoptotic cell death in Bid-deficient mice occurs relatively normally and Biddeficient mice do not have the same severe phenotypes as do knockouts of other members of the extrinsic signaling pathway (such as caspase 8, 41 Fadd, 42,43 or Fas-deficient mice 44 ) also argues for the existence of a compensatory mechanism or molecule in addition to Bid.…”

Mechanisms of apoptosis by c-Myc

“…TNF family receptors use an adaptor system to directly activate caspases and they are subject to complex modulation (Ashkenazi and Dixit, 1998). Ligand binding causes receptor homotrimerization and recruitment on the cytoplasmic face of the membrane of a death-inducing signaling complex (DISC), which includes the adaptors FADD and TRADD and procaspase-8 as crucial physiological death e ectors (Juo et al, 1998;Varfolomeev et al, 1998;Yeh et al, 1998;Zhang et al, 1998). A brief outline of the CD95/ Fas and TNf receptor systems follows since c-Myc has been implied to act both upstream and downstream of each (Janicke et al, 1994;Klefstrom et al, 1994Klefstrom et al, , 1997Hueber et al, 1997;Wang et al, 1998a).…”

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

“…98 FADD-deficient mice die in utero, suggesting that FADD also plays a role in nonlymphoid tissue proliferation. 99 Future studies are required to reveal a more detailed view about the function of HIPKs in death receptor signalling and their role in FADD phosphorylation.…”