Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms

Morgan, Michael J.; Thorburn, Jacqueline; Pandolfi, Pier Paolo; Thorburn, Andrew

doi:10.1083/jcb.200204039

Cited by 80 publications

(84 citation statements)

References 53 publications

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“…Apoptosis through TRADD-DD overexpression is in part inhibited by Bcl-X L , a mitochondria-localised antiapoptotic member of the Bcl-2 protein family, and relies on p53 and PML expression. 87 These results imply that a pathway targeting the mitochondria is involved in this death mechanism. The physiological relevance and the exact molecular mechanism of TRADD-DDinduced apoptosis remain to be determined in the future.…”

Section: Traddmentioning

confidence: 93%

“…87 In the cytoplasm, TRADD serves as an adaptor molecule for the recruitment of FADD and caspase-8 to the TNF-R1 DISC. 70 In the nuclear compartment, TRADD is found in association with PML-NBs.…”

Section: Traddmentioning

confidence: 99%

“…70 In the nuclear compartment, TRADD is found in association with PML-NBs. 87 The isolated DD of TRADD, which also mediates the interaction with the TNF-R1 DD, 70,88 is responsible for PML-NB localisation and is sufficient to initiate a caspaseindependent form of cell death. Apoptosis through TRADD-DD overexpression is in part inhibited by Bcl-X L , a mitochondria-localised antiapoptotic member of the Bcl-2 protein family, and relies on p53 and PML expression.…”

Section: Traddmentioning

confidence: 99%

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

2003

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Promyelocytic leukaemia (PML) nuclear bodies (NBs) are macromolecular nuclear domains present in virtually every mammalian cell. PML nuclear bodies (PML-NBs) were functionally linked to various fundamental cellular processes, including transcriptional control, tumour suppression and apoptosis regulation. Supporting the important function of PML and its associated NBs in apoptosis regulation, several apoptotic regulators localise to PML-NBs, and cells from PMLdeficient mice show severe apoptotic defects, including induction of genotoxic stress and death receptor CD95 (Fas/ APO-1) activation. Based on the current literature, we hypothesise that PML-NBs regulate apoptosis through different molecular mechanisms, on the one hand by acting as macromolecular scaffolds for recruitment and post-translational modification of the apoptotic key regulator p53, and on the other by regulating the subcellular bioavailability and quality of some apoptotic signal transducers.

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Section: Traddmentioning

confidence: 93%

Section: Traddmentioning

confidence: 99%

Section: Traddmentioning

confidence: 99%

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

2003

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“…Expression of full-length TRADD in the presence of the CRM-1-dependent nuclear export inhibitor leptomycin B traps TRADD in the nucleus and activates an apoptotic pathway that depends upon this alternate subcellular localization. 18 Expression of the core helices of the death domain aa 222-289 (nuclear TRADD), which contains the nuclear import sequence but no export sequence, results in an exclusively nuclear localized protein that kills cells when it is in the nucleus but cannot kill cells when it is forced outside the nucleus. 18 As the established FADD and caspase-8-dependent pathway occurs in the cytoplasm, we hypothesized that apoptosis induced by nuclear TRADD may occur by a different mechanism.…”

Section: Introductionmentioning

confidence: 99%

The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm

et al. 2005

Cell Death Differ

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TNFR1 associated death domain protein (TRADD) contains an N-terminal TRAF binding domain and a C-terminal death domain along with nuclear import and export sequences that cause shuttling between the cytoplasm and nucleus. The death domain of TRADD contains the nuclear import sequence and expression of the core death domain (nuclear TRADD) results in exclusive nuclear localization and activation of a distinct apoptotic pathway. Cytoplasmic TRADD activates apoptosis through Fas-associated death domain protein (FADD) and caspase-8 activation that was blocked by caspase inhibitors or dominant-negative FADD. These inhibitors did not inhibit death induced by nuclear TRADD, which could only be inhibited by combining caspase inhibitors and a serine protease inhibitor. The pathway activated by nuclear TRADD requires caspase-9 catalytic activity. However, apoptosis activating factor deficiency confers only partial protection from death. This pathway represents an alternate means by which TRADD can regulate cell death independently of FADD and caspase-8 that occurs from the nucleus rather than the cytoplasm.

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“…21 In addition to FADD, another adapter protein, TRADD, forms DEFs. 38 Thus, our study adds FAF1 to the previously known DEF components, caspase-8, FADD and TRADD. We are interested to know whether FAF1 just supplements FADD's function or if it can substitute for FADD in DEF assembly.…”

Section: Discussionmentioning

confidence: 97%

Fas‐associated factor‐1 mediates chemotherapeutic‐induced apoptosis via death effector filament formation

Park

Ryu

Kim

et al. 2005

Intl Journal of Cancer

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Fas-associated factor-1 (FAF1) is a newly introduced member of the Fas death-inducing signaling complex and potentiates Fas-mediated apoptosis. Clinical study has revealed that FAF1 is significantly reduced in gastric carcinomas. The present study demonstrates that FAF1 mediates chemotherapeutic-induced apoptosis via participation in the formation of death effector filament (DEF), a cytoskeleton-like structure found in receptor-independent apoptosis. Overexpression of FAF1 enhanced DEF assembly and cell death induced by chemotherapeutics such as staurosporine (STS), cisplatin (CDDP) and etoposide (VP16). FAF1 sensitized cells to STS, CDDP and VP16 in dose-and timedependent manner. Introduction of antisense FAF1 construct inhibited DEF assembly and chemotherapeutic-induced apoptosis. Analysis using FAF1 truncates showed that the FAF1 domain interacting with DEDs of FADD and caspase-8 was sufficient to enhance DEF assembly. Confocal microscopy revealed that FAF1 was present in DEFs together with FADD and caspase-8. Collectively, our data provide a molecular mechanism for the chemosensitization by FAF1 (i.e., mediating DEF assembly). ' 2005 Wiley-Liss, Inc.Key words: Fas-associated factor-1; chemotherapeutic; sensitization; apoptosis; death effector filament Apoptosis can be initiated via receptor-dependent and receptorindependent signaling pathways. [1][2][3][4] In the receptor-dependent apoptosis (or extrinsic) pathway, the TNFR superfamily, including Fas, TNFR and DRs, plays a critical role in the transmission of apoptotic signals. [5][6][7][8][9] Apoptosis induced by chemotherapeutic agents (intrinsic pathway), such as CDDP, STS and VP16, occurs independently of receptors. 1,2,10 A key event in this pathway is the formation of apoptosome, a complex composed of cytochrome c, APAF1 and caspase-9, which in turn activates effector caspases (caspase-3, -6 and -7). 11-13 Therefore, caspase-9, rather than caspase-8, has been emphasized in receptor-independent apoptosis. However, studies demonstrating that chemotherapy triggers caspase-8-dependent apoptosis stress the importance of caspase-8 in receptor-independent apoptosis. 10,[14][15][16][17][18] Formation of DEFs, which are novel cytoskeleton-like structures formed by self-assembly of DEDs, has been reported as a mechanism of receptor-independent apoptosis by caspase-8. [19][20][21][22][23] DEFs are found in chemotherapeutic-treated cells. 16 DEF assembly leads to recruitment of other DED or DED-like domain-containing proteins such as FADD, caspase-2 and caspase-10, triggering the molecular cascade of apoptosis. 20,21,24 DEFs are localized in the perinucleus and appear as cage-or lariat-like structures. Antiapoptotic DED-containing v-FLIPs, such as MC159 and E8, block formation of DEFs as well as DED-induced apoptosis. [19][20][21]23 FAF1 is a Fas-binding protein and a member of the Fas-DISC. 25,26 Although FAF1 does not contain typical domains related to cell death, its N-terminus binds to the DD of Fas, the DEDID of FAF1, the caspase-8-DEDs and the FADD DED. 25,...

show abstract

Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms

Cited by 80 publications

References 53 publications

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

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

The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm

Fas‐associated factor‐1 mediates chemotherapeutic‐induced apoptosis via death effector filament formation

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