Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN-deficient mice

Kreder, Dirk; Krut, Oleg; Adam‐Klages, Sabine; Wiegmann, Katja; Scherer, Gudrun; Plitz, Tom; Jensen, Jens‐Michael; Proksch, Ehrhardt; Steinmann, Jörg; Pfeffer, Klaus; Krönke, Martin

doi:10.1093/emboj/18.9.2472

Cited by 76 publications

(95 citation statements)

References 31 publications

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“…Studies using truncated mutants of the cytoplasmic domain of the 55-kDa TNF receptor (TNFR-55) have identified a cytoplasmic region (designated NSD, for neutral SMase activation domain) of this receptor, which is distinct from the death domain and contains a small sequence of 10 amino-acid residues that is necessary for activation of NSmase . The role of FAN in TNF signaling has been confirmed on cells derived from FAN knockout mice, which display defects in ceramide generation and apoptosis (Kreder et al, 1999).…”

Section: Biochemical Pathways Of Ceramide Generationmentioning

confidence: 93%

Radiation and ceramide-induced apoptosis

2003

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Section: Biochemical Pathways Of Ceramide Generationmentioning

confidence: 93%

Radiation and ceramide-induced apoptosis

2003

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“…169 FAN interacts with one of its five WD-repeats with a nine AA stretch of TNF-R1 located directly in the membrane-proximal region of the DD and appears involved in the activation of the neutral sphingomyelinase (nSMase). 169,170 Defects in cutaneous barrier repair have been found in mice with a genetic deletion of FAN. 170 The role of nSMase-derived ceramide is largely undefined, especially as at least in some cells nSMase becomes only activated very transiently during only the first 3 min of TNF stimulation.…”

Section: Tradd-independent Signalling Pathwaysmentioning

confidence: 99%

“…169,170 Defects in cutaneous barrier repair have been found in mice with a genetic deletion of FAN. 170 The role of nSMase-derived ceramide is largely undefined, especially as at least in some cells nSMase becomes only activated very transiently during only the first 3 min of TNF stimulation. 171 A proapoptotic function of nSMase has been described in one report using a dominant-negative form of FAN, 172 whereas ERK1/2 and phospholipase A2 activation are not linked to FAN.…”

Section: Tradd-independent Signalling Pathwaysmentioning

confidence: 99%

Tumor necrosis factor signaling

2003

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A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50 000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed.

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“…En accord avec cette hypothèse, la surexpression dans des cellules COS de la protéine FAN sauvage potentialise une activité sphingomyélinase neutre en réponse au TNF, tandis que la forme tronquée, agissant comme un dominant négatif, prévient ce phénomène [1]. Des études réalisées à partir de fibroblastes et de thymocytes issus de souris déficitaires en FAN ont confirmé le rôle de cette protéine dans le contrôle de l'activation d'une sphingomyélinase neutre par le TNF [6]. Enfin, la surexpression dans des fibroblastes humains transformés par l'antigène T de SV40, d'une forme tronquée de FAN agissant comme dominant négatif, abolit l'activation de la voie sphingomyéline-céramide consécutive à l'engagement du TNF-RI [7].…”

Section: La Protéine Fan Est Nécessaire à L'activation D'une Sphingomunclassified

“…Toutefois, ces souris présentent des anomalies cutanées, notamment un défaut de réparation de la barrière épider-mique, qui sont corrélées avec une prolifération ralentie des kératino-cytes. Ceci suggère un rôle de la protéine FAN dans le contrôle de l'homéostasie de l'épiderme [6]. Il semblerait que le déficit en protéine FAN s'accompagne d'autres modifications phénotypiques.…”

Section: Rôle De Fan In Vivounclassified