The Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK)-Fibroblast Growth Factor-inducible 14 (Fn14) Signaling System Regulates Glioma Cell Survival via NFκB Pathway Activation and BCL-XL/BCL-W Expression

Tran, Nhan L.; McDonough, Wendy S.; Savitch, Benjamin A.; Sawyer, Thomas F.; Winkles, Jeffrey A.; Berens, Michael E.

doi:10.1074/jbc.m409906200

Cited by 170 publications

(184 citation statements)

References 68 publications

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“…Selective deletion of PPAR␤/␦ in these different cell types will likely lead to a better understanding of this novel regulation. Overexpression of TWEAK receptor can independently lead to enhanced NF-B activity, 47 and greatly enhanced expressions of this protein was detected in CCl 4 -treated mouse liver as compared with similarly treated wild-type mouse liver. Although not examined in the current study, there is evidence that PPAR␤/␦ can also modulate gene expression by repressing transcription.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2008

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Potential functional roles for the peroxisome proliferator-activated receptor-␤/␦ (PPAR␤/␦) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPAR␤/␦ is expressed in liver, its function in this tissue is less clear. To determine the role of PPAR␤/␦ in chemically induced liver toxicity, wild-type and PPAR␤/␦-null mice were treated with azoxymethane (AOM) and markers of liver toxicity examined. Bile duct hyperplasia, regenerative hyperplasia, and increased serum alanine aminotransferase (ALT) were found in AOM-treated PPAR␤/␦-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl 4 ) hepatoxicity was also observed in PPAR␤/␦-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl 4 were observed between wild-type or PPAR␤/␦-null mice in response to CCl 4 . Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-B) activity were noted in PPAR␤/␦-null mice. Conclusion:Results from these studies show that PPAR␤/␦ is protective against liver toxicity induced by AOM and CCl 4 , suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue. (HEPATOLOGY 2008;47:225-235.)

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Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2008

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“…This small membrane protein is able to mediate a variety of intracellular signals in a cellspecific fashion including apoptosis, necrosis, proliferation, and survival (17,22,31,43). Proliferative signals elicited by Fn14 are likely to be mediated by association of TNFR-associated factor proteins with the Fn14 cytoplasmic domain and subsequent stimulation of NF-B activity (29,30), whereas survival signals involve NF-B-mediated up-regulation of Bcl-XL and Bcl-W expression (44). Death signals initiated by Fn14 have been thoroughly studied in tumor cell lines and have been shown to involve caspase activation as well as cathepsin B-dependent necrosis (31).…”

Section: Discussionmentioning

confidence: 99%

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

Felli

Pedini

Zeuner

et al. 2005

The Journal of Immunology

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IFN-γ inhibits the growth and differentiation of erythroid precursor cells and mediates hemopoietic suppression through mechanisms that are not completely understood. We found that treatment of human erythroid precursor cells with IFN-γ up-regulates the expression of multiple members of the TNF family, including TRAIL and the recently characterized protein TWEAK. TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) were expressed by purified erythroblasts at all the stages of maturation. Exposure to recombinant TWEAK or agonist anti-Fn14 Abs was able to inhibit erythroid cell growth and differentiation through caspase activation. Because other members of the TNF family such as TRAIL and CD95 ligand (CD95L) are known to interfere with erythroblast growth and differentiation, we investigated the role of different TNF/TNFR family proteins as potential effectors of IFN-γ in the immature hemopoietic compartment. Treatment of erythroid precursor cells with agents that blocked either TRAIL, CD95L, or TWEAK activity was partially able to revert the effect of IFN-γ on erythroid proliferation and differentiation. However, the simultaneous inhibition of TRAIL, TWEAK, and CD95L resulted in a complete abrogation of IFN-γ inhibitory effects, indicating the requirement of different receptor-mediated signals in IFN-γ-mediated hemopoietic suppression. These results establish a new role for TWEAK and its receptor in normal and IFN-γ-mediated regulation of hematopoiesis and show that the effects of IFN-γ on immature erythroid cells depend on multiple interactions between TNF family members and their receptors.

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“…30 FN14 binds TRAF1, 2, 3 and 5, and TWEAK signalling induces TRAF2-dependent activation of both the canonical and noncanonical NF-kB transcription pathways [31][32][33] which can regulate cytokine and pro-survival gene transcription. In particular, TWEAK induced NF-kB activation has been directly implicated in mesangial cell chemokine secretion, 26 glioma cell survival 23 and myoblast differentiation. 15 However, as suggested above, it appears that TWEAK can also elicit pro-death signalling in some cell types.…”

Section: The Involvement Of Tweak and Fn14 In Cell Deathmentioning

confidence: 99%

“…For example, overexpression of TWEAK in HEK293 cells substantially increases tumour growth and vascularization in athymic mice, 22 and a recent study demonstrated that treatment of glioma cells with TWEAK significantly reduced camptothecin and TRAIL induced apoptosis in an FN14 dependent manner. 23 The proposed mechanism was that FN14 signalling mediated the activation of NF-kB, which resulted in the upregulation of the antiapoptotic proteins Bcl-xL and Bcl-w. Similarly, TWEAK treatment promotes endothelial cell survival when grown in limiting media.…”

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confidence: 99%

TWEAK shall inherit the earth

Vince

Silke

2006

Cell Death Differ

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Sometimes size really does not matter: recent papers on the tumour necrosis factor (TNF)-like ligand, TWEAK (tumour necrosis factor-like weak inducer of apoptosis), and its diminutive 129 amino-acid receptor, FN14 (fibroblast growth factor (FGF) -inducible 14 kDa protein), describe an impressive and potent range of biological effects. The TNF superfamily (TNSF) receptor FN14 has a small cytoplasmic domain, and the limited similarity of its extracellular domain to the cysteine-rich domains of the TNFSF receptors was only appreciated retrospectively when it was discovered that it bound TWEAK. 1 Recent work has demonstrated that TWEAK knockout animals have an activated immune system that is skewed by elevated numbers of natural killer (NK) cells and responds lethally to bacterial endotoxins, but also shows a powerful ability to prevent tumour growth. 2 Other topical papers show that TWEAK and FN14 work to promote liver regeneration following injury and prevent the differentiation of a diverse range of cell types. The role of TWEAK and FN14 in cancer has yet to be conclusively established, but several groups have observed high expression of FN14 in cancerous tissues, and demonstrated that it can promote cellular functions important for tumorigenesis, including cytokine production, cellular proliferation, survival, migration and angiogenesis. 3 TWEAK is a type II transmembrane protein (extracellular C-terminus) that can undergo proteolysis to produce an active soluble homotrimer, 4,5 whereas FN14 is a type Ia transmembrane protein. 6 In some respects the potent effects of the ligand TWEAK are reminiscent to those of TNFa: both factors appear to play roles in inflammation, and both have the capacity to induce cell death, although usually in conjunction with another stimulus. Responses to TNFSF ligands can be complex because several ligands often bind to the same receptor and vice versa. For example, both the human ligands TNFa and LTa bind the receptors TNFR1 and TNFR2, whereas LTa also binds HVEM. In fact, more than half of the TNSF ligands bind to at least two receptors. 7 One of the amazing things about the TWEAK/FN14 system is that it is a simple, single ligand, single receptor system 7 in which the intracellular signalling domain of FN14 is only 28 amino acids. It remains possible that another TWEAK receptor exists 8 which might help to explain the diverse range of effects that TWEAK produces, but this is yet to be conclusively established.

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The Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK)-Fibroblast Growth Factor-inducible 14 (Fn14) Signaling System Regulates Glioma Cell Survival via NFκB Pathway Activation and BCL-XL/BCL-W Expression

Cited by 170 publications

References 68 publications

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

TWEAK shall inherit the earth

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