Fas-associated protein with death domain (FADD), an adaptor that bridges death receptor signaling to the caspase cascade, is indispensible for the induction of extrinsic apoptotic cell death. Interest in the non-apoptotic function of FADD has greatly increased due to evidence that FADD-deficient mice or dominant-negative FADD transgenic mice result in embryonic lethality and an immune defect without showing apoptotic features. Numerous studies have suggested that FADD regulates cell cycle progression, proliferation, and autophagy, affecting these phenomena. Recently, programmed necrosis, also called necroptosis, was shown to be a key mechanism that induces embryonic lethality and an immune defect. Supporting these findings, FADD was shown to be involved in various necroptosis models. In this review, we summarize the mechanism of extrinsic apoptosis and necroptosis, and discuss the in vivo and in vitro roles of FADD in necroptosis induced by various stimuli.[BMB Reports 2012; 45(9): 496-508] INTRODUCTIONFas-associated protein with death domain (FADD) is a critical adaptor protein for death receptor (DR)-mediated apoptosis. FADD is composed of two domains called the death domain (DD) and death effector domain (DED). The DD of FADD binds to the DD of the death receptor and FADD recruits procaspase-8 through the DED-DED interaction, forming a death-inducing signaling complex (DISC), where procaspase-8 is activated by self-cleavage. Active caspase-8 cleaves downstream effector caspases such as caspase-3, -6, and -7, inducing apoptosis. Interestingly, FADD deficiency results in embryonic lethality, displaying a defect in immune homeostasis and immune cell proliferation despite the defect in inducing apoptosis. In addition, FADD is also implicated in non-apoptotic functions such as cell cycle progression, proliferation, autophagy, inflammation and innate immunity (1, 2). Particularly, FADD phosphorylation at Ser194 (pFADD) by several kinases is associated with its nuclear localization and cell cycle regulation (3-8). Although FADD and pFADD are often overexpressed in various tumors, their functions in cancer development or chemotherapy-sensitivity are still controversial (9-14). Recent strong evidence from in vivo mice studies suggested negative roles of FADD in RIP1-and RIP3-dependent necroptosis (15-18). DR-mediated caspase-8 activation requires FADD, and leads to the cleavage of RIP1, RIP3, and CYLD, preventing necroptosis (19)(20)(21)(22). Thus, FADD deficiency is thought to inhibit caspase-8 and subsequent apoptosis, but activate necroptosis. Since necroptosis can be initiated by various stimuli in a variety of cell types independently of DRs, the exact mechanisms and functions of FADD require further investigation. This review focuses on the recent discoveries about the roles of FADD in apoptosis and necroptosis in various models, and we refer the reader to two comprehensive reviews of the diverse functions of FADD (1, 2). EXTRINSIC APOPTOSIS Molecular mechanism of extrinsic apoptosisExtrinsic apoptosis, which is...

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Randomly microphase-separated graft copolymers have been self-reorganized so as to exhibit a micellar structure with excellent connectivity upon tuning the solvent affinity. These copolymers are used as a structure-directing agent for organized mesoporous TiO(2) films with no grain boundaries, leading to enhanced solar conversion efficiency of dye-sensitized solar cells.

Polyvinylpyrrolidone (PVP)-coated iron oxide nanoparticles were prepared by the thermal decomposition of Fe(CO)(5) (iron pentacarbonyl) in one step. X-ray diffraction (XRD), transmission electron microscopy (TEM), electrophoretic light scattering (ELS), infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) together with the variation of the molar ratio of PVP/Fe(CO)(5), solvent, and molecular weight of PVP, were used to characterize the PVP-coated iron oxide nanoparticles. Fifty to hundred nanometer-sized iron oxide nanoclusters with a spherical shape were formed in dimethylformamide (DMF), used as a solvent, and exhibited an enhanced stability in the aqueous media. Their magnetic properties were investigated by superconducting quantum interface device (SQUID). The in vitro cytotoxicity test revealed that the PVP-coated iron oxide nanoparticles exhibited excellent biocompatibility by MTT assay. Magnetic resonance imaging (MRI) effect was observed with the administration of PVP-coated iron oxide nanoparticles through the marginal vein of rabbit, resulting in improved detection of the liver lesions.

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