1α,25-Dihydroxyvitamin D3 Protects Human Keratinocytes from Apoptosis by the Formation of Sphingosine-1-Phosphate

Manggau, Marianti A.; Kim, Dong-Seok; Ruwisch, Lars; Vogler, Rüdiger; Schäfer‐Korting, Monika; Kleuser, Burkhard; Körting, Hans Christian

doi:10.1046/j.0022-202x.2001.01496.x

Cited by 121 publications

(109 citation statements)

References 46 publications

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“…Exogenous S1P triggers many important cellular responses including proliferation (24,25), differentiation (47), cytoprotection (48), and cell migration (49). It has been extensively documented that S1P binds to specific cell surface receptors the endothelial differentiation gene receptors (Edg) (26), which have now been renamed to S1P [1][2][3][4][5] receptors (27).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Cross-activates the Smad Signaling Cascade and Mimics Transforming Growth Factor-β-induced Cell Responses

Xin

Ren

Kleuser

et al. 2004

Journal of Biological Chemistry

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171

143

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Exposure of renal mesangial cells to sphingosine 1-phosphate (S1P) leads to a rapid and transient activation of the mitogen-and stress-activated protein kinases but also the protein kinase B. Here, we show that S1P also induces phosphorylation of Smad proteins, which are members of the transforming growth factor-␤ (TGF-␤) signaling device. However, Smad phosphorylation occurred more slowly with a maximal effect after 20 -30 min of S1P stimulation when compared with the rapid activation of the MAPKs. Interestingly, Smad phosphorylation is increased by pertussis toxin, which is in contrast to the complete inhibition of S1P-induced MAPK phosphorylation by pertussis toxin. TGF-␤ is a potent anti-inflammatory cytokine, which in mesangial cells attenuates the expression of (i) inducible nitricoxide synthase (iNOS) caused by interleukin (IL)-1␤, (ii) secreted phospholipase A 2 (sPLA 2 ), and (iii) matrix metalloproteinase-9 (MMP-9). These gene products are also down-regulated by S1P in a concentration-dependent manner. Furthermore, the expression of connective tissue growth factor is enhanced by both TGF-␤ 2 and S1P. These effects of S1P are not mediated by the MAPK cascade as neither pertussis toxin nor the MAPK cascade inhibitor U0126 are able to reverse this inhibition. Overexpression of the inhibitory Smad-7 or down-regulation of co-Smad-4 lead to a reversal of the blocking effect of S1P on IL-1␤-induced NO release. Moreover, down-regulating the TGF-␤ receptor type II by the siRNA technique or antagonizing the S1P 3 receptor subtype with suramin abrogates S1P-stimulated Smad phosphorylation. In summary, our data show that S1P trans-activates the TGF-␤ receptor and triggers activation of Smads followed by activation of connective tissue growth factor gene transcription and inhibition of IL-1␤-induced expression of iNOS, sPLA 2 , and MMP-9.

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Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Cross-activates the Smad Signaling Cascade and Mimics Transforming Growth Factor-β-induced Cell Responses

Xin

Ren

Kleuser

et al. 2004

Journal of Biological Chemistry

Self Cite

171

143

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“…This is also clarified by the fact that the antiapoptotic effect of 1,25(OH) 2 D 3 can be completely suppressed by addition of the sphingosinkinase-inhibitor N,Ndimethylsphingosine. 39 In contrast, pharmacological concentrations of 1,25(OH) 2 The development of many types of skin cancer, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is induced by UV-exposure. 16 Whereas the total UV-dose added up in the exposed skin area during lifetime is responsible for the genesis of SCC, 7 the origin of BCC is presumed both in the total UV-dose added up in the exposed skin area during lifetime and in higher intermittent UV-doses.…”

Section: Immunmodulatory Effects In the Skinmentioning

confidence: 99%

“…To the contrary, physiological concentrations of 1,25(OH) 2 D 3 generate an apoptosis-resistance against ceramides, ultraviolet radiation and tumor necrosis factor-α (TNF-α). 39 The cytoprotective/antiapoptotic effect of 1,25(OH) 2 D 3 is obviously linked to the development of sphingosine-1-phosphate. This is also clarified by the fact that the antiapoptotic effect of 1,25(OH) 2 D 3 can be completely suppressed by addition of the sphingosinkinase-inhibitor N,Ndimethylsphingosine.…”

Section: Immunmodulatory Effects In the Skinmentioning

confidence: 99%

From the bench to emerging new clinical concepts

Trémezaygues

Reichrath

2011

Dermato-Endocrinology

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“…For example, 1,25(OH) 2 D 3 modulates the expression of genes involved in S1P degradation, such as Sphingosine-1-phosphate phosphatase 2 (SGPP2) [182] and of growth factors involved in differentiation and neuroprotection, such as NT-3, Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) [3,4]. On the other hand, many neuroprotective actions of 1,25(OH) 2 D 3 have been reported to be due to stimulation of SphK and increased levels of S1P [183,184]. In addition, 1,25(OH) 2 D 3 also is able to decrease the expression of CerK, the enzyme that generates C1P [18].…”

Section: Cross Talk Between Vitamin D and Sphingolipid Metabolismmentioning

confidence: 99%

Vitamin D and Sphingolipids: Role in Bone and Neural System

Frati¹,

Gil²,

Pierucci³

et al. 2017

A Critical Evaluation of Vitamin D - Basic Overview

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Abstract1-Alpha,25-dihydroxyvitamin D3 (1,25(OH) 2 D 3 ) is known to play an important physiological role on growth and differentiation in a variety of nonmalignant and malignant cell types through classical actions, mediated by its specific receptor (VDR), and nongenomic actions resulting in the activation of specific signalling pathways. Due to the broad distribution of Vitamin D Receptor (VDR) in many tissues and the ability of 1,25(OH) 2 D 3 to regulate fundamental processes, such as cell proliferation and differentiation, this steroid hormone has been suggested in the treatment of different diseases, from cancer to neurodegenerative diseases. In fact, structural 1,25(OH) 2 D 3 analogues, with weaker collateral effects, have recently entered in clinical trials. Other interesting molecules due to their pleiotropic actions are the bioactive sphingolipids (SLs), in particular ceramide (Cer) and sphingosine 1-phosphate (S1P). Cells maintain a dynamic balance of these metabolites since Cer and sphingoid bases mediate cell death, while S1P exerts mitogenic effects and promotes differentiation of several cell types including osteogenic and neural cells. The biological actions of 1,25(OH) 2 D 3 and SLs, in particular S1P, share many common effectors, including calcium regulation, growth factor expression, inflammatory cytokines, etc., but whether they could act synergistically is still unknown and deserves further investigation.

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1α,25-Dihydroxyvitamin D3 Protects Human Keratinocytes from Apoptosis by the Formation of Sphingosine-1-Phosphate

Cited by 121 publications

References 46 publications

Sphingosine 1-Phosphate Cross-activates the Smad Signaling Cascade and Mimics Transforming Growth Factor-β-induced Cell Responses

Sphingosine 1-Phosphate Cross-activates the Smad Signaling Cascade and Mimics Transforming Growth Factor-β-induced Cell Responses

From the bench to emerging new clinical concepts

Vitamin D and Sphingolipids: Role in Bone and Neural System

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