Screening, identification, and functional analysis of three novel missense mutations in the TRADD gene in children with ALL and ALPS

Dechant, Markus Johann; Scheuerpflug, Christian Gerold; Pauly, Eva; Bosch, Jutte van der Werff ten; Debatin, Klaus‐Michael; Fellenberg, Jörg

doi:10.1002/pbc.21672

Cited by 3 publications

(3 citation statements)

References 36 publications

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“…S6a-c). These data are consistent with previous reports showing that the level of TRADD mRNA decreases as prostate cancer progresses 44 , and that missense TRADD mutations occur in acute lymphocytic leukaemia 45 and squamous cell carcinoma of the lung 46 . On the basis of these findings and the results of our study, we propose that TRADD has a tumour-suppressive role mediated through its stabilization of ARF protein (Supplementary Fig.…”

Section: Tradd Is a Tumour Suppressor Candidate In Human Cancerssupporting

confidence: 93%

TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation

et al. 2012

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Tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) protein is a central adaptor in the TNFR1 signalling complex that mediates both cell death and inflammatory signals. Here, we report that Tradd deficiency in mice accelerated tumour formation in a chemical-induced carcinogenesis model independently of TNFR1 signalling. In vitro, primary cells lacking TRADD were less susceptible to HRas-induced senescence and showed a reduced level of accumulation of the p19(Arf) tumour suppressor protein. Our data indicate that TRADD shuttles dynamically from the cytoplasm into the nucleus to modulate the interaction between p19(Arf) and its E3 ubiquitin ligase ULF, thereby promoting p19(Arf) protein stability and tumour suppression. These results reveal a previously unknown tumour-suppressive role for nuclear TRADD, augmenting its long-established cytoplasmic functions in inflammatory and immune signalling cascades. Our findings also make an important contribution to the rapidly expanding field of p19(Arf) post-translational regulation.

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Section: Tradd Is a Tumour Suppressor Candidate In Human Cancerssupporting

confidence: 93%

TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation

et al. 2012

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“…These CD4 Ϫ CD8 Ϫ "doublenegative" T cells are described in FasL-mutant gld mice, 16 lpr Fas-mutant 26 and Fas Ϫ/Ϫ mice, 27 and cFLIP transgenic mice 28 ; and just as we have shown in B6.GT mice, they are present in large numbers in B6.lpr/lpr.Bim Ϫ/Ϫ mice. [29][30][31] They are also in humans with autoimmune lymphoproliferative syndrome (ALPS), most of whom have mutations in FasL, Fas, 32 caspase-8, 33 or caspase-10, 34 or missense mutations in TNFR-associated death domain, 35 causing defective lymphocyte apoptosis. The DN cells are classed as T cells because they express CD3 and TCR, even though they express B220, a molecule historically used to define murine B cells but also expressed on apoptotic T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice

Sedger

Katewa

Pettersen

et al. 2010

Blood

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To delineate the relative roles of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand in lymphocyte biology and lymphoproliferative disease, we generated mice defective in both molecules. B6.GT mice develop severe polyclonal lymphoproliferative disease because of accumulating CD3 ؉ CD4 ؊ CD8 ؊ B220 ؉ T cells, CD4 ؉ and CD8 ؉ T cells, and follicular B cells, and mice die prematurely from extreme lymphocytosis, thrombocytopenia, and hemorrhage. IntroductionApoptotic cell death is mediated primarily by 2 distinct pathways: the intrinsic mitochondrial-sensed, Bcl2-family regulated pathway and the extrinsic death-ligand/receptor pathway. Members of the tumor necrosis factor (TNF) family of death-inducing ligands, such as Fas ligand (FasL), TNF, and TNF-related apoptosis-inducing ligand (TRAIL), compose the extrinsic pathway, and these molecules bind to specific receptors that contain a "death-domain" signature in their cytoplasmic region. For FasL and TRAIL, ligand binding results in recruitment of Fas-associated death domain adaptor protein to the receptor's death domain enabling subsequent recruitment and activation of procaspase-8 and/or procaspase-10. Apical caspases then act on downstream effector caspases that leads to degradation of the inhibitor of the caspase-activated DNase, with cleavage of dsDNA causing apoptotic cell death. 1 To date, however, the specific roles and redundancies of the multiple death TNF-family death ligands and receptors are unclear.Despite the conservation in intracellular death receptor signaling, the biologic functions of TNF/TNFR molecules in vivo appear to be divergent. TNF-␣ is an important mediator of inflammation 2 and a key cause of apoptosis of virus-infected cells, 3 and FasL/Fas plays a critical role in the elimination of self-reactive lymphocytes and in regulating T cell homeostasis. 4 In contrast, the physiologic role of TRAIL in vivo is still emerging. TRAIL specifically kills transformed 5 and virally infected cells 6 and controls tumor growth and metastasis contributing to tumor surveillance. [7][8][9][10] The inert properties of LZ-TRAIL on normal cells 5,11 has led to Apo2L/ TRAIL protein and agonistic receptor-specific antibodies being trialed for the treatment of human cancers. However, it is debatable whether TRAIL's tumoricidal activity provides sufficient evolutionary pressure for its existence as the fourth death ligand/receptor system in humans. That cancer most frequently occurs in persons after child-bearing age and that TNF-␣ and FasL also have tumorigenic properties 12,13 suggest that TRAIL/TRAIL-Rs mediates biologic functions that remain to be defined. Curiously, the study of TRAIL Ϫ/Ϫ mice revealed little about the roles of TRAIL in vivo as these mice are essentially physiologically normal. 7 It is now apparent that, because most cells that express TRAIL also express FasL 14 and because TRAIL and FasL initiate a death-signaling pathway that is almost identical, 15 attempts to define the physiologic role of TRAIL/TRAIL-Rs in vi...

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“…These effects all seem to be unrelated to the pro-apoptotic functions of FADD and CASP8 but reflect their ability to prevent necroptosis [ 51 , 52 , 1434 , 1450 , 1451 , 1456 – 1458 ]. Corroborating these findings, loss-of-function mutations in FADD [ 1459 – 1462 ], CASP8 or CASP10 [ 1463 – 1465 ] and TRADD [ 1466 ] have been associated with ALPS-like syndromes and hematological diseases in humans. Of note, patients with ALPS bearing mutations in FADD or CASP8 but not ALPS patients with mutations in FAS or FASLG also exhibit immunodeficiency coupled with lymphocytic infiltrations in multiple organs, granulomas and/or inflammatory bowel disease [ 1459 , 1463 , 1467 – 1469 ].…”

Section: Extrinsic Apoptosis In Diseasementioning

confidence: 98%

Apoptotic cell death in disease—Current understanding of the NCCD 2023

et al. 2023

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Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

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Screening, identification, and functional analysis of three novel missense mutations in the TRADD gene in children with ALL and ALPS

Abstract: Mutations in the TRADD gene may contribute to the development of different hematological diseases. The identified mutations demonstrate a putative impact on TRADD signaling and cell survival but may not mainly explain the pathology of the diseases investigated.

Cited by 3 publications

References 36 publications

TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation

TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation

Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice

Apoptotic cell death in disease—Current understanding of the NCCD 2023

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