JNK, but not MAPK, activation is associated with Fas‐mediated apoptosis in human T cells

Wilson, David J.; Fortner, Karen A.; Lynch, David H.; Mattingly, Raymond R.; Macara, Ian G.; Posada, James; Budd, Ralph C.

doi:10.1002/eji.1830260505

Cited by 139 publications

(100 citation statements)

References 45 publications

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“…The inhibition of ERK below a basal threshold level is reported to trigger apoptosis in HeLa cells with activation of p38 kinase but not SAPK/JNK (49). The inhibition of ERK activity and the concomitant activation of SAPK/JNK and p38 kinase has been reported in apoptosis of nerve growth factor-deprived PC12 cells (22), Fas-stimulated Jurkat cells (15,24), and UV-irradiated mouse fibroblasts (25). Thus, it seems that the ability of a cell to die or survive may be dictated by a critical balance between the ERK and the SAPK/ JNK and p38 pathway (26).…”

Section: Discussionmentioning

confidence: 95%

“…In addition, the inhibition of ERK activity has been reported to correlate with the activation of SAPK/JNK and p38 kinase as well as with the induction of apoptosis in nerve growth factor-deprived PC12 pheochromocytoma cells (22), Fas-induced Jurkat cells (15,24), and UVirradiated mouse fibroblasts (25), and the balance between the activity of the stress kinases to that of ERK has been proposed to determine cell fate (26), because the Raf1-ERK signaling pathway plays a pivotal role in suppressing apoptotic death (27,28).…”

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confidence: 99%

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Activation of Stress-activated Protein Kinase/c-Jun NH2-terminal Kinase and p38 Kinase in Calphostin C-induced Apoptosis Requires Caspase-3-like Proteases but Is Dispensable for Cell Death

Ozaki

Tani

Ikemoto

et al. 1999

Journal of Biological Chemistry

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Apoptosis was induced in human glioma cell lines by exposure to 100 nM calphostin C, a specific inhibitor of protein kinase C. Calphostin C-induced apoptosis was associated with synchronous down-regulation of Bcl-2 and Bcl-x L as well as activation of caspase-3 but not caspase-1. The exposure to calphostin C led to activation of stress-activated protein kinase/c-Jun NH 2 -terminal kinase (SAPK/JNK) and p38 kinase and concurrent inhibition of extracellular signal-regulated kinase (ERK). Upstream of ERK, Shc was shown to be activated, but its downstream Raf1 and ERK were inhibited. The pretreatment with acetyl-Tyr-Val-Ala-Asp-aldehyde, a relatively selective inhibitor of caspase-3, or benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.fmk), a broad spectrum caspase inhibitor, similarly inhibited calphostin C-induced activation of SAPK/JNK and p38 kinase as well as apoptotic nuclear damages (chromatin condensation and DNA fragmentation) and cell shrinkage, suggesting that caspase-3 functions upstream of SAPK/JNK and p38 kinase, but did not block calphostin C-induced surface blebbing and cell death. On the other hand, the inhibition of SAPK/JNK by transfection of dominant negative SAPK/JNK and that of p38 kinase by SB203580 induced similar effects on the calphostin Cinduced apoptotic phenotypes and cell death as did z-VAD.fmk and acetyl-Tyr-Val-Ala-Asp-aldehyde, but the calphostin C-induced PARP cleavage was not changed, suggesting that SAPK/JNK and p38 kinase are involved in the DNA fragmentation pathway downstream of caspase-3. The present findings suggest, therefore, that the activation of SAPK/JNK and p38 kinase is dispensable for calphostin C-mediated and z-VAD.fmk-resistant cell death.It has been expected that signal transduction pathways involving specific protein kinases are involved in mediating apoptosis. Extracellular signal-regulated kinase (ERK) 1 is most strongly stimulated by activation of protein-tyrosine kinase receptors (1) and also activated by both Ras-dependent (2-4) and Ras-independent signalings (5) in response to activation of G protein-coupled receptors, and common intermediates in intracellular signaling cascades are involved in diverse cellular functions including growth and differentiation (6). Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate results in the activation of Raf1 (7) and ERK (8 -11) within minutes, suggesting the involvement of PKC in the signaling pathway leading to ERK activation. In addition, Ras functions as an essential transducer of various physiological signals leading to cell growth and proliferation in a PKC-dependent or PKC-independent manner (12), and activated Ras also renders cells susceptible to apoptosis after depression of PKC activity (13,14).SAPK/JNK and p38 kinase have been proposed to mediate apoptosis, but a number of reports have challenged the notion that the activation of SAPK/JNK and/or p38 kinase is sufficient to induce apoptosis (15-21), and the integration and balance of SAPK/JNK and p38 pathways probably contribute to commitment to a...

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Activation of Stress-activated Protein Kinase/c-Jun NH2-terminal Kinase and p38 Kinase in Calphostin C-induced Apoptosis Requires Caspase-3-like Proteases but Is Dispensable for Cell Death

Ozaki

Tani

Ikemoto

et al. 1999

Journal of Biological Chemistry

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“…These results indicate that activation of Krs proteins is dependent on caspase activity and necessary for apoptosis induction by MT-21 (Figure 9). Activation of JNK has been observed to correlate with the apoptosis induction of various stimuli, including nerve growth factor withdrawal, B-cell receptor cross-linking and Fas ligation (Xia et al, 1995;Cahill et al, 1996;Graves et al, 1996;Wilson et al, 1996;Juo et al, 1997). Caspase inhibitors can block JNK activation induced by Fas cross-linking, indicating that this pathway may function downstream of caspase activation (Cahill, et al, 1996;Juo et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of JNK has also been observed to correlate with apoptosis inducing agents, as well as nerve growth factor withdrawal, B-cell receptor crosslinking and Fas ligation (Xia et al, 1995;Cahill et al, 1996;Wilson et al, 1996). Caspase inhibitors block JNK activation induced by Fas cross-linking, indicating that JNK functions on downstream of the caspase cascade (Cahill et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis

1999

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Fas is a well characterized apoptosis-inducing factor. One of our synthetic compounds, MT-21, induced apoptosis in human leukemia HL-60 cells similar to Fas. MT-21 activated caspase-3, an important cysteine aspartic protease for apoptosis induction. MT-21 also activated c-Jun-NH 2 -terminal kinase (JNK), a member of mitogen activated protein kinase (MAPK) superfamily that is involved in the regulation of cell growth, di erentiation and cell death. Moreover, MT-21 treatment resulted in the activation of a 36 kDa kinase which uses myelin basic protein (MBP) as a substrate. However, MAPK and p38 were not activated by treatment with MT-21. The 36 kDa MBP kinase was shown to be a proteolytic product derived from the Krs protein with a molecular weight of 60 kDa. The Krs protein is a Ser/Thr protein kinase whose activity is enhanced by digestion of its C-terminal regulatory domain by caspase-3. When a kinase-inactive mutant form of Krs protein was overexpressed in HL-60 cells, JNK activation and apoptosis induction by MT-21 were suppressed. Furthermore, overexpression of dominant negative c-Jun also suppressed apoptosis induction by MT-21. These ®ndings indicate that MT-21 induces apoptosis by the activation of JNK via the Krs protein, which is activated by caspase cleavage.

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“…Thus, optimal stimulation of JNK1 and JNK2 phosphorylation was not required for Fas stimulation of apoptosis in BAF3 cells. Expression of a kinase-inactive JNK inhibited Fasmediated apoptosis in neuroblastoma cells (Goillot et al, 1997) and Fas-induced apoptosis was also prevented by forskolin which blocked JNK activation (Wilson et al, 1996). However, expression of a dominant negative form of SEK1, an activator of JNK, had little e ect on Fas-mediated apoptosis (Lenczowski et al, 1997) and thymocytes from sek1 7/7 mice were more susceptible to Fas-mediated cell death than wild type cells (Nishina et al, 1997).…”

Section: Jnk1/2 Phosphorylation Is Not Necessary For Fas-mediated Kilmentioning

confidence: 99%

JNK activation is not required for Fas-mediated apoptosis

et al. 1999

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Fas ligation in the presence of cycloheximide induced Jun N-terminal kinase 1 (JNK1) and JNK2 phosphorylation, caspase activation and cell death in the IL-3-dependent cell line BAF3. Fas-mediated apoptosis was prevented by expression of dominant negative FADD but not inhibited by IL-3. To investigate the role of JNK activation in this process, we examined cells overexpressing a JNK-speci®c phosphatase M3/6. M3/6 prevented Fas stimulation of JNK, but did not a ect Fas-mediated caspase activation or cell death, demonstrating that JNK activation is not required for these processes.

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JNK, but not MAPK, activation is associated with Fas‐mediated apoptosis in human T cells

Cited by 139 publications

References 45 publications

Activation of Stress-activated Protein Kinase/c-Jun NH2-terminal Kinase and p38 Kinase in Calphostin C-induced Apoptosis Requires Caspase-3-like Proteases but Is Dispensable for Cell Death

Activation of Stress-activated Protein Kinase/c-Jun NH2-terminal Kinase and p38 Kinase in Calphostin C-induced Apoptosis Requires Caspase-3-like Proteases but Is Dispensable for Cell Death

Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis

JNK activation is not required for Fas-mediated apoptosis

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