In Vivo Localization of Fas-Associated Death Domain Protein in the Nucleus and Cytoplasm of Normal Thyroid and Liver Cells

FADD (Fas-associated death domain) is the main death receptor adaptor molecule that transmits apoptotic signal. Recently, FADD protein was shown to be expressed both in the cytoplasm and nucleus of in vitro cell lines. In contrast to the cytoplasmic FADD, the nuclear FADD was shown to protect cells from apoptosis. However, in vivo subcellular localization of FADD was still unknown. Here, we demonstrated that FADD protein was expressed in both cytoplasmic and nuclear compartment in ex vivo thyroid cells demonstrating that nuclear sublocalization of FADD protein was a relevant phenomenon occurring in vivo. Moreover, we showed that in the nucleus of untransformed thyroid cells FADD localized mainly on euchromatin. We confirmed the nuclear localization of FADD in ex vivo liver and showed that in this organ FADD and MBD4 interact together. These results demonstrate that FADD is physiologically expressed in the nucleus of cells in at least two mouse organs. This particular localization opens new possible role of FADD in vivo either asan inhibitor of cell death, or as a transcription factor, or as a molecular link between apoptosis and genome surveillance

FADD at the Crossroads between Cancer and Inflammation

International audienceInitially described as an adaptor molecule for death receptor (DR)-mediated apoptosis, Fas-associated death domain (FADD) was later implicated in nonapoptotic cellular processes. During the last decade, FADD has been shown to participate and regulate most of the signalosome complexes, including necrosome, FADDosome, innateosome, and inflammasome. Given the role of these signaling complexes, FADD has emerged as a new actor in innate immunity, inflammation, and cancer development. Concomitant to these new roles, a surprising number of mechanisms deemed to regulate FADD functions have been identified, including post-translational modifications of FADD protein and FADD secretion. This review focuses on recent knowledge of the biological roles of FADD, a pleiotropic molecule having multiple partners, and its impact in cancer, innate immunity, and inflammation

FADD adaptor in cancer.

FADD (Fas Associated protein with Death Domain) is a key adaptor molecule transmitting the death signal mediated by death receptors. In addition, this multiple functional protein is implicated in survival/proliferation and cell cycle progression. FADD functions are regulated via cellular sublocalization, protein phosphorylation, and inhibitory molecules. In the present review, we focus on the role of the FADD adaptor in cancer. Increasing evidence shows that defects in FADD protein expression are associated with tumor progression both in mice and humans. Better knowledge of the mechanisms leading to regulation of FADD functions will improve understanding of tumor growth and the immune escape mechanisms, and could open a new field for therapeutic interventions

Modulatory role of the anti-apoptotic protein kinase CK2 in the sub-cellular localization of Fas associated death domain protein (FADD)

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PPILOW, a European project dedicated to welfare in Poultry and PIg Low-input outdoor and Organic production systems - Newsletter issue 5

Newsletter du projet PPILO

Characterization and functional consequences of underexpression of clusterin in rheumatoid arthritis

We previously compared by microarray analysis gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) tissues. Among the set of genes identified as a molecular signature of RA, clusterin (clu) was one of the most differentially expressed. In the present study we sought to assess the expression and the role of CLU (mRNA and protein) in the affected joints and in cultured fibroblast-like synoviocytes (FLS) and to determine its functional role. Quantitative RT-PCR, Northern blot, in situ hybridization, immunohistochemistry, and Western blot were used to specify and quantify the expression of CLU in ex vivo synovial tissue. In synovial tissue, the protein was predominantly expressed by synoviocytes and it was detected in synovial fluids. Both full-length and spliced isoform CLU mRNA levels of expression were lower in RA tissues compared with OA and healthy synovium. In synovium and in cultured FLS, the overexpression of CLU concerned all protein isoforms in OA whereas in RA, the intracellular forms of the protein were barely detectable. Transgenic overexpression of CLU in RA FLS promoted apoptosis within 24 h. We observed that CLU knockdown with small interfering RNA promoted IL-6 and IL-8 production. CLU interacted with phosphorylated IkappaBalpha. Differential expression of CLU by OA and RA FLS appeared to be an intrinsic property of the cells. Expression of intracellular isoforms of CLU is differentially regulated between OA and RA. We propose that in RA joints, high levels of extracellular CLU and low expression of intracellular CLU may enhance NF-kappaB activation and survival of the synoviocytes