Molecules in focusFADD/MORT1, a signal transducer that can promote cell death or cell growth
Introduction
Members of the TNF-R family of receptors have pleiotropic activities in mammalian cells. The same receptor can trigger cell proliferation, cell differentiation or cell death depending on the responding cell type and/or its metabolic state (reviewed by Ref.[1]). For example, CD95 plays an essential role in removing chronically activated lymphocytes by apoptotic cell death, but has also been reported to transmit a costimulatory signal in antigen-stimulated quiescent T-cells. Further, TNF-RI plays a critical role in liver regeneration following partial hepatectomy, yet transmits a death signal in many types of cultured tumour cells (reviewed by[1]). A protein–protein interaction motif, called a `death domain', is present in the intracellular portion of several TNF-R family members (e.g. CD95, TNF-RI, DR3) and is essential for apoptosis signalling by these receptors (reviewed by Ref.[1]).
Section snippets
Structure
The human and mouse FADD/MORT1 genes were cloned from cDNA expression libraries derived from HeLa cells, human B lymphocytes or mouse T-lymphocytes, in yeast-two-hybrid screens designed to identify proteins that interact with the cytoplasmic region of CD952, 3, 4. FADD/MORT1 binds only to wild-type CD95 but not to signalling-deficient mutants of this receptor, consistent with the notion that it is a critical signal transducer.
The human FADD/MORT1 gene is composed of two exons (286 and 341 base
Expression, subcellular localisation and posttranslational modification
Northern blot and in situ hybridisation analyses showed that FADD/MORT1 mRNA is expressed at relatively high levels in essentially all adult and embryonic tissues in both mice and humans3, 13. In untreated cells FADD/MORT1 protein localises to the cytosol, but upon CD95 ligation it is rapidly recruited to the plasma membrane where it forms an integral part of the CD95 `death inducing signalling complex' (DISC)[14]. A substantial fraction of FADD/MORT1 molecules is phosphorylated by a presently
Biological function
The biological function of FADD/MORT1 was investigated in experiments with cultured cell lines or transgenic mice expressing a dominant-interfering mutant of this protein[15]and in FADD/MORT1-deficient mice generated by targeted disruption of the corresponding gene13, 16. A dominant-interfering mutant of FADD/MORT1 was produced by deletion of the NH2-terminal `death effector domain' (Fig. 1b and Fig. 2 grey boxes). This truncated protein, here referred to as FADD-DN, competes with wild-type
Possible medical applications
Abnormalities in the regulation of apoptosis are implicated as a cause or contributing factor in many diseases. The protracted survival of cells that are normally doomed (e.g. activated lymphocytes) can be an early event in tumourigenesis[19]or lead to autoimmune disease[20]. Conversely, premature death of cells that are normally long-lived, such as for instance neurons, can be a cause of degenerative disorders. Since FADD/MORT1 is essential for apoptosis signalling from CD95 and some of its
Acknowledgements
Work in our laboratory is supported by fellowships from the Leukemia Society of America and Melbourne University and grants from the NHMRC (Canberra), the Dr. Josef Steiner Cancer Research Foundation (Bern), the Cancer Research Institute (New York) and the Anti-Cancer Council of Victoria (Melbourne).
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The first cloned sea cucumber FADD from Holothuria leucospilota: Molecular characterization, inducible expression and involvement of apoptosis
2019, Fish and Shellfish ImmunologyCitation Excerpt :Previous studies have suggested that the requirement to FADD in innate immune against invading pathogens may be evolutionarily conserved from Drosophila to mammals [21,22]. In contrast to the detailed descriptions of the biological roles of FADD in mammals [1–8,20,23–26], little is known regarding the function of FADD in invertebrates, with an exception of Drosophila [21,27–33]. The FADD orthologs are widely found in invertebrates.
Localization of apoptotic and proliferating cells and mRNA expression of caspases and Bcl-2 in gonads of chicken embryos
2014, Acta HistochemicaCitation Excerpt :One upstream pathway, promoted by the activation of several members of the tumor necrosis factor receptor (TNF-R) family, results in the processing of the initiator caspase-8 and/or caspase-10. Fas-induced cell death is mediated by the recruitment and activation of caspase-8 via Fas-associated death domain (FADD) (Strasser and Newton, 1999). The alternative pathway involving an initiator caspase occurs after a perturbation of the mitochondria, which promotes the release of mitochondrial cytochrome C (Ekert et al., 2001).
The transcription factor FOXM1 (Forkhead box M1): Proliferation-specific expression, transcription factor function, target genes, mouse models, and normal biological roles
2013, Advances in Cancer ResearchCitation Excerpt :Since Shh is an activating upstream signal for GLI-1 in the Hedgehog pathway (Hui & Angers, 2011; Ingham, 2008; Ingham, Nakano, & Seger, 2011; Jiang & Hui, 2008; Ribes & Briscoe, 2009; Riobo & Manning, 2007; Rohatgi & Scott, 2007; Ruiz i Altaba, Mas, & Stecca, 2007; Ryan & Chiang, 2012; Varjaluso & Taipale, 2007, 2008; Wang, McMahon, & Allen, 2007), Shh may increase the FOXM1 expression via activation of GLI-1, which suggests that foxm1 may be a target gene of the Hedgehog pathway (Calvisi et al., 2009; Schüller et al., 2007; Teh et al., 2002). In addition to its prominent function in apoptosis, FADD (Fas (CD95, DR2 (death receptor 2))-associated death domain) plays a role in T-cell proliferation (Budd, 2002; Strasser & Newton, 1999; Tourneur & Chiocchia, 2010). Human FADD is phosphorylated by CKIα (casein kinase Iα) at S-194 (Alappat et al., 2005), which is equivalent to S-191 in murine FADD.
Chrysin sensitizes tumor necrosis factor-α-induced apoptosis in human tumor cells via suppression of nuclear factor-kappaB
2010, Cancer LettersCitation Excerpt :Caspase activation is the central machinery in apoptosis. TNFα mediates apoptotic cell death via the cell death receptor pathway initiates from caspase 8 activation [27]. In this study, no caspase 8 activation was observed in cells treated with either chrysin or TNF-α alone, while chrysin pretreatment significantly enhanced caspase 8 cleavage in TNFα-treated cells (Fig. 2C).