Activation of the Sphingomyelin Cycle Through the Low-Affinity Neurotrophin Receptor

Dobrowsky, Rick T.; Werner, Mark H.; Castellino, Alexander M.; Chao, Moses V.; Hannun, Yusuf A.

doi:10.1126/science.8079174

Cited by 577 publications

(381 citation statements)

References 42 publications

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“…A number of extracellular stimuli, not only various cytokines including tumor necrosis factor (TNF)-a, interferon-g (Kim et al, 1991;Dressler et al, 1992), interleukin-1b (Ballou et al, 1992), nerve growth factor (Dobrowsky et al, 1994), and activators of Fas receptor (Cifone et al, 1994), but also physical stresses including heat shock, irradiation and chemotherapeutic drugs (Verheij et al, 1996;Santana et al, 1996;Ja rezou et al, 1996) are shown to cause sphingomyelin (SM) hydrolysis via sphingomyelinase (SMase), leading to elevation of intracellular ceramide, although several recent reports have questioned the role of ceramide in apoptosis induced by Fas or TNF-a (Sillence and Allen, 1997; Hsu et al, 1998;Watts et al, 1997Watts et al, , 1999a. The addition of exogenous ceramide has been associated with several antiproliferative responses including cell di erentiation, apoptosis, and cell cycle arrest (Okazaki et al, 1990;Kolesnick and Hannun, 1999).…”

Section: Introductionmentioning

confidence: 99%

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

et al. 2000

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Ceramide has recently been regarded as a potential mediator of apoptosis. In the present study, the e ects of Bcl-2 and Bax on the ceramide-mediated apoptotic pathways were examined in glioma cells overexpressing Bcl-2 or Bax. Etoposide, cisplatin and tumor necrosis factor-a induced apoptosis of C6 rat glioma cells which was associated with ceramide formation due to activation of neutral sphingomyelinase, followed by release of mitochondrial cytochrome c into the cytosol and activation of caspases-9 and -3. The growth of C6 cells stably overexpressing either Bcl-2 or Bax was almost equal to that of the vector-transfected cells. Bax overexpression enhanced etoposide-induced apoptosis through acceleration of cytochrome c release and caspases activation. However, Bax had no e ect on ceramide formation. Similar ®ndings were obtained in C6 cells and U87-MG human glioblastoma cells which were transiently overexpressed with Bax. In contrast, Bcl-2 overexpression resulted in a retardation of the apoptotic process via prevention of cytochrome c release and caspases activation, and ceramide formation was also blocked when Bcl-2 was highly overexpressed in glioma cells. In addition, transient overexpression of Bcl-xL also exerted inhibitory e ects on ceramide formation and apoptotic cell death induced by etoposide. These results indicate that Bax promotes apoptosis regardless of ceramide formation and that Bcl-2 or Bcl-xL prevents ceramide formation by repressing neutral sphingomyelinase as well as ceramide-induced cytochrome c release.

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Section: Introductionmentioning

confidence: 99%

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

et al. 2000

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“…p75 NTR has been shown to enhance NGF binding and signaling through TrkA (51)(52)(53)(54). p75 NTR also initiates signal transduction separately from TrkA (55)(56)(57). There is increasing evidence that the signals generated by p75 NTR promote programmed cell death (58)(59)(60)(61) rather than prevent it, as does TrkA (62).…”

Section: Resultsmentioning

confidence: 99%

A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA

Grimes

Beattie²,

Mobley³

1997

Proc. Natl. Acad. Sci. U.S.A.

159

138

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The topology of signal transduction is particularly important for neurons. Neurotrophic factors such as nerve growth factor (NGF) interact with receptors at distal axons and a signal is transduced by retrograde transport to the cell body to ensure survival of the neuron. We have discovered an organelle that may account for the retrograde transport of the neurotrophin signal. This organelle is derived from endocytosis of the receptor tyrosine kinase for NGF, TrkA. In vitro reactions containing semi-intact PC12 cells and ATP were used to enhance recovery of a novel organelle: small vesicles containing internalized NGF bound to activated TrkA. These vesicles were distinct from clathrin coated vesicles, uncoated primary endocytic vesicles, and synaptic vesicles, and resembled transport vesicles in their sedimentation velocity. They contained 10% of the total bound NGF and almost one-third of the total tyrosine phosphorylated TrkA. These small vesicles are compelling candidates for the organelles through which the neurotrophin signal is conveyed down the axon.

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“…As for specific sets of neurons, 53 p75 LNGFR may modulate the interaction of a defined NT to its specific Trk receptor on bone marrow stromal cells. p75 LNGFR also signals on its own 54 and triggers neuronal apoptosis in the absence of NGF-induced TrkA activation. 55,56 The generation of TK ϩ or TK-receptor isoforms, which retain NT high-affinity binding sites, may also modulate the local function of NT.…”

Section: Discussionmentioning

confidence: 99%

Expression of Neurotrophins and their Receptors in Human Bone Marrow

Labouyrie

Dubus

Groppi

et al. 1999

The American Journal of Pathology

164

104

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The expression of neurotrophins and their receptors, the low-affinity nerve growth factor receptor (p75 LNGFR ) and the Trk receptors (TrkA , TrkB, and TrkC) , was investigated in human bone marrow from 16 weeks fetal age to adulthood. Using reverse transcription-polymerase chain reaction , all transcripts encoding for catalytic and truncated human TrkB or TrkC receptors were detected together with trkAI transcripts , whereas trkAII transcripts were found only in control nerve tissues. Transcripts for the homologue of the rat truncated TrkC(ic113) receptor were identified for the first time in human tissue. Stromal adventitial reticular cells were found immunoreactive for all neutrophin receptors. In contrast, hematopoietic cell types were not immunoreactive for p75 LNGFR Nerve growth factor (NGF) 1 is the prototype of a family of related neurotrophic factors known as neurotrophins (NT), which also includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4, also called neurotrophin-5 or NT-5 in humans) (reviewed in Lindsay et al 2 ). NT are trophic factors for the growth, differentiation, and survival of specific subsets of neurons in the developing and mature nervous system. 2 NT can interact with two classes of receptors with distinct ligand affinity and specificity. The low-affinity nerve growth factor receptor, p75 LNGFR , binds all known NT. 3,4 Tyrosine kinase receptors of the Trk family are essential components of NT high-affinity binding sites that trigger neuronal survival, growth, and differentiation. 5 TrkA is the preferred receptor for NGF 6,7 but has a lower efficiency for NT-3 or NT-4/5. TrkB is bound by BDNF and NT-4 and, to a lesser extent, by 9 TrkC is characterized by a unique ligand, NT-3. 10 In some cell lines, TrkA is sufficient to form high-affinity binding sites through homodimerization, 7 whereas p75 LNGFR potentiates TrkA activation by NGF in the PC12 cell line. 11 Variants of tyrosine kinase receptors (TK ϩ ) with insertions in either the extracellular domain (ECD) or the tyrosine kinase domain have been identified for trkA 12,13 and trkC [13][14][15][16] in both human and rat.Truncated receptors lacking the kinase domain (TK Ϫ ) have been described for TrkB and TrkC but not for TrkA. [15][16][17][18] These receptors may function as dominant negative isoforms or immunoadhesins. 13,19,20 Both TK ϩ and TK Ϫ receptors have been detected in neurons while only truncated TrkB and TrkC isoforms have been detected primarily in nonneuronal cells. [15][16][17][18]21 The expression of functional NGF receptors has been detected in several bone marrow-derived cells such as monocytes, 22 mastocytes, 23,24 and B or T cell clones. [25][26][27][28] Among its pleiotropic effects, NGF induces platelet shape changes, 29 triggers monocyte cytotoxic activity, 22 and induces basophilic cell differentiation 30 -32 and mast cell development and degranulation. 24,33 However, NGF receptors have not been consistently detected on bone marrow cells. Although trkA and p75 L...

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Activation of the Sphingomyelin Cycle Through the Low-Affinity Neurotrophin Receptor

Cited by 577 publications

References 42 publications

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA

Expression of Neurotrophins and their Receptors in Human Bone Marrow

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