A Dominant Negative Fas-associated Death Domain Protein Mutant Inhibits Proliferation and Leads to Impaired Calcium Mobilization in Both T-cells and Fibroblasts

Hueber, Anne-Odile; Zörnig, Martin; Bernard, Anne‐Marie; Chautan, Magali; Evan, Gérard I.

doi:10.1074/jbc.275.14.10453

Cited by 71 publications

(56 citation statements)

References 72 publications

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“…T-cell compartment. 26 The influence of such a FADD-dependent signaling pathway on proliferation is not restricted to T cells 31,32 and supports further data linking nonapoptotic death receptor signaling to proliferation. ( 33,34 and references therein).…”

supporting

confidence: 70%

Transgenic overexpression of a dominant negative mutant of FADD that, although counterselected during tumor progression, cooperates in L‐myc‐induced tumorigenesis

Hueber¹,

Bösser²,

Zörnig³

2004

Intl Journal of Cancer

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Key words: FADD-DN; death receptor; cell cycle; oncogene cooperationApoptosis as a special form of programmed cell death has been recognized as a fundamental process both throughout embryogenesis and in the adult organism to maintain tissue homeostasis and remove dangerous or surplus cells without inflammation. 1 For a cancer to occur and progress, apoptosis must be inhibited as the tumor cells are constantly exposed to a variety of apoptotic stimuli, e.g., overexpression of apoptosis-inducing oncogenes, hypoxia or lack of survival signals after detachment of metastatic cells from the tumor mass (anoikis). 2 Furthermore, conventional treatment of cancer by chemotherapy and irradiation is based on the selective induction of apoptosis in tumor cells, and tumor resistance to such treatment is a result of the inhibition of drug-or radiation-induced apoptosis. 3 The extrinsic apoptotic pathway is triggered by so-called death receptors, which together with their ligands belong to the TNF/ TNFR superfamily. The death receptor subfamily consists of CD95/Fas/Apo-1, TNFR1, DR3 and the TRAIL receptors DR4/ DR5, DR6, NGFR and EDAR. 4 Death receptors contain in their intracellular part a specific protein-binding motif, the DD, which mediates homophilic interactions with other DD-bearing proteins. FADD is essential for death receptor-induced apoptosis as it is used as an adaptor protein by several DD-containing death receptors. [5][6][7][8][9][10][11][12][13][14][15] In the activated CD95 receptor, FADD binds with its N-terminal DD to the CD95 DD. FADD then recruits the apical caspase-8 via another protein-binding domain in its C terminus, the DED. Within this assembled intracellular receptor complex (DISC 16 ), caspase-8 becomes activated ("induced proximity" 17 ) and starts to proteolyse its targets.Death receptor-mediated cell killing is normally induced by the death receptor ligands and plays an important role during physiological cell death as well as in different antitumor strategies (e.g., cytotoxic T-cell killing 18 ). Consequently, several mutations have been identified in tumors which lead to impairment of death receptor-induced apoptosis. 1,19 Examples include overexpression of the inhibitory FLIP proteins in melanomas, 20 transcriptional downregulation of caspase-8 mRNA by gene deletion or promoter methylation 21 and CD95 mutations in different cancers. [22][23][24] Direct proof of the tumor-suppressing proapoptotic activity of the CD95 receptor has been obtained by in vivo cooperation experiments. Tumor development in L-myc transgenic mice is accelerated when mice are bred onto a CD95-deficient lpr background. 25 Interference with FADD functionality leads to the expected impairment of death receptor killing. 26 -30 Surprisingly, however, not only cell death but also T-cell proliferation is strongly inhibited in lck FADD-DN transgenic mice 28 -30 and in rag1 -/-k.o. animals reconstituted with a FADD -/-k.o. T-cell compartment. 26 The influence of such a FADD-dependent signaling pathway on proliferation is not re...

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supporting

confidence: 70%

Transgenic overexpression of a dominant negative mutant of FADD that, although counterselected during tumor progression, cooperates in L‐myc‐induced tumorigenesis

Hueber¹,

Bösser²,

Zörnig³

2004

Intl Journal of Cancer

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“…Cell concentration was estimated as in Figure 1 towards TRAIL tested so far showed additional proliferation by treatment with TRAIL (data not shown). As FADD might signal proliferation (Hueber et al, 2000), JURKAT cells expressing the dominant-negative form of FADD were included, which also showed TRAILmediated proliferation to 113% within 24 h (data not shown), suggesting that neither Caspase-8 nor FADD are involved in TRAIL-mediated proliferation. Thus, inhibition of apoptosis by disruption of receptor proximal signaling may allow TRAIL-induced survival and proliferation.…”

Section: Trail-induced Proliferation In Cancer Cellsmentioning

confidence: 99%

TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-κB

et al. 2003

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“…In addition, peripheral Tcells and immature T-cell progenitors that lack FADD (Zhang et al, 1998(Zhang et al, , 2001 or overexpress the dominantnegative FADD mutant protein (Newton et al, 1998;Walsh et al, 1998Walsh et al, , 2000Zornig et al, 1998) display defective proliferation in vivo. In vitro studies using fibroblasts (Hueber et al, 2000), myeloid progenitors (Pellegrini et al, 2005), or breast epithelial cells (Alappat et al, 2003) have yielded similar results. The mechanisms through which FADD acts to induce cell proliferation rather than apoptosis are not well-understood, but may be related to its subcellular distribution and/or phosphorylation (O'Reilly et al, 2004;Zhang et al, 2004).…”

Section: Introductionmentioning

confidence: 70%

Impaired lactation in mice expressing dominant‐negative FADD in mammary epithelium

Shackleton

O’Reilly

Sutherland

et al. 2009

Developmental Dynamics

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The Fas-associated death domain (FADD/Mort1) adaptor protein was originally identified as a key mediator of apoptosis, although pleiotropic functions for FADD have also been reported. FADD-mediated tumoricidal effects have been described in breast cancer cells; however, its physiological role in normal mammary gland epithelium is not well understood. To determine the role of FADD signaling during mammary gland development, we generated transgenic mice overexpressing dominant-negative FADD (DN-FADD) in mammary epithelium, using the steroid responsive mouse mammary tumor virus promoter. Transgenic mice exhibited a perturbation in lactation resulting in impaired milk production and pup growth retardation. Reduced expansion of alveoli was evident during early lactation with extensive shedding of luminal alveolar cells. Significantly more TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labeling)-positive cells were present at this time point and a subsequent increase in bromodeoxyuridine-positive cells was observed. These findings suggest a role for FADD in maintaining the survival of mammary secretory alveolar cells after the establishment of lactation.

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A Dominant Negative Fas-associated Death Domain Protein Mutant Inhibits Proliferation and Leads to Impaired Calcium Mobilization in Both T-cells and Fibroblasts

Cited by 71 publications

References 72 publications

Transgenic overexpression of a dominant negative mutant of FADD that, although counterselected during tumor progression, cooperates in L‐myc‐induced tumorigenesis

Transgenic overexpression of a dominant negative mutant of FADD that, although counterselected during tumor progression, cooperates in L‐myc‐induced tumorigenesis

TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-κB

Impaired lactation in mice expressing dominant‐negative FADD in mammary epithelium

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