Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis

Verheij, Marcel; Bose, Ron; Lin, Xiaochen; Yao, Bei; Jarvis, W. D.; Grant, Steven; Birrer, Michael J.; Szabó, Éva; Zon, Leonard I.; Kyriakis, John; Haimovitz‐Friedman, Adriana; Fuks, Zvi; Kolesnick, Richard

doi:10.1038/380075a0

Cited by 1,722 publications

(1,415 citation statements)

References 27 publications

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“…Thus, upregulation of OSBP in response to oxLDL-IC could lead to enhanced conversion of ceramide to sphingomyelin. It has been established that cellular accumulations of ceramide, which occur as a result of oxidative stress or in response to inflammatory cytokines, are associated with apoptotic responses (26). We have recently found that indeed short chain ceramides decreased in response to oxLDL-IC compared to controls (data not shown).…”

Section: Genes Similarly Regulated By Ox-ldl-ic and Klh-icmentioning

confidence: 74%

Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells

et al. 2009

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Objective-To compare the global effects of oxidized LDL (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) on gene expression in human monocytic cells and to identify differentially expressed genes involved with inflammation and survival.Methods and Results-U937 cells were treated with oxLDL-IC, oxLDL, Keyhole limpet hemocyanin immune complexes (KLH-IC), or vehicle for 4 h. Transcriptome profiling was performed using DNA microarrays. oxLDL-IC uniquely affected the expression of genes involved with pro-survival (RAD54B, RUFY3, SNRPB2, and ZBTB24). oxLDL-IC also regulated many genes in a manner similar to KLH-IC. Functional categorization of these genes revealed that 39% are involved with stress responses, including the unfolded protein response which impacts cell survival, 19% with regulation of transcription, 10% with endocytosis and intracellular transport of protein and lipid, and 16% with inflammatory responses including regulation of I-κB/NF-κB cascade and cytokine activity. One gene in particular, HSP70 6, greatly up-regulated by ox-LDL-IC, was found to be required for the process by which oxLDL-IC augments IL1-β secretion. The study also revealed genes uniquely up-regulated by oxLDL including genes involved with growth inhibition (OKL38, NEK3, and FTH1), oxidoreductase activity (SPXN1 and HMOX1), and transport of amino acids and fatty acids (SLC7A11 and ADFP).Conclusions-These findings highlight early transcriptional responses elicited by oxLDL-IC that may underlie its cytoprotective and pro-inflammatory effects. Cross-linking of Fcγ receptors appears to be the trigger for most of the transcriptional responses to oxLDL-IC. The findings further strengthen the hypothesis that oxLDL and oxLDL-IC elicit disparate inflammatory responses and play distinct roles in the process of atherosclerosis.

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Section: Genes Similarly Regulated By Ox-ldl-ic and Klh-icmentioning

confidence: 74%

Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells

et al. 2009

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“…It has been reported that activation of the JNK pathway contributes to the induction of apoptosis. JNK signaling is required for ceramide-mediated apoptosis in U937 cells (Sawai et al, 1995;Verheij et al, 1996). JNK also regulates apoptosis of human …”

Section: Discussionmentioning

confidence: 99%

Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells

et al. 1999

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Bufalin, a component of the Chinese medicine chan'su, induces apoptosis in various lines of human tumor cells, such as leukemia HL60 and U937 cells, by altering the expression of apoptosis-related genes, for example, bcl-2 and c-myc. In this study, we characterized a gene that is involved in bufalin-induced apoptosis by the di erential display (DD) technique. The partial nucleotide sequence of one of the di erentially expressed clones obtained after treatment with bufalin was identical to that of the human gene for Tiam1. When U937 cells were treated with 10 77 M bufalin, expression of both Tiam1 mRNA and the protein was induced 1 h after the start of the treatment. The increase of Tiam1 mRNA was transient but the level of Tiam1 protein continued to increase at least for 6 h. In addition, the activities of Rac1 and p21-activated kinase (PAK) were also stimulated by bufalin treatment. To evaluate the role of Tiam1 in the apoptotic process, we examined the e ects of the expression of sense and antisense RNA for Tiam1 in U937 cells. Apoptosis was strongly induced by bufalin in cells that expressed sense RNA for Tiam1 as compared to apoptosis in control cells treated with bufalin only. Cells expressing antisense RNA for Tiam1 were signi®cantly more resistant than the control bufalin-treated cells to induction of DNA fragmentation in response to bufalin. Moreover, sense transformants had elevated activities of PAK and c-Jun NH 2 -terminal kinase (JNK). These results suggest that Tiam1 might play a critical role in bufalin-induced apoptosis through the activation of Rac1, PAK, and JNK pathway.

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“…FAST and RICK (also known as RIP2) kinases are also implicated in Fas-mediated apoptosis (Tian et al, 1995;Inohara et al, 1998;McCarthy et al, 1998). Various apoptotic stimuli such as Fas, TNF-a, ceramide and stresses induce activation of c-Jun N-terminal kinase (JNK), also known as stress activated protein kinase (SAPK) (Hibi et al, 1993;Derijard et al, 1994;Verheij et al, 1996;Xia et al, 1995). This suggests the involvement of the JNK pathway in the apoptotic signaling.…”

Section: Introductionmentioning

confidence: 99%

Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity

et al. 1999

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We have identi®ed and characterized a new calcium/ calmodulin (Ca 2+ /CaM) dependent protein kinase termed death-associated protein kinase 2 (DAPK2) that contains an N-terminal protein kinase domain followed by a conserved CaM-binding domain with signi®cant homologies to those of DAP kinase, a protein kinase involved in apoptosis. DAPK2 mRNA is expressed abundantly in heart, lung and skeletal muscle. The mapping results indicated that DAPK2 is located in the central region of mouse chromosome 9. In vitro kinase assay revealed that DAPK2 is autophosphorylated and phosphorylates myosin light chain (MLC) as an exogenous substrate. DAPK2 binds directly to CaM and is activated in a Ca 2+ /CaM-dependent manner. A constitutively active DAPK2 mutant is generated by removal of the CaMbinding domain (DCaM). Treatment of agonists that elevate intracellular Ca 2+ -concentration led to the activation of DAPK2 and transfection studies revealed that DAPK2 is localized in the cytoplasm. Overexpression of DAPK2, but not the kinase negative mutant, signi®cantly induced the morphological changes characteristic of apoptosis. These results indicate that DAPK2 is an additional member of DAP kinase family involved in apoptotic signaling.

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Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis

Cited by 1,722 publications

References 27 publications

Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells

Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells

Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells

Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity

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