JNK is involved in signal integration during costimulation of T lymphocytes

Su, Bing; Jacinto, Estela; Hibi, Masahiko; Kallunki, Tuula; Karin, Michael; Ben‐Neriah, Yinon

doi:10.1016/0092-8674(94)90056-6

Cited by 864 publications

(741 citation statements)

References 51 publications

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“…These results suggest that at the doses the cis-DDP produces cytotoxicity, JNK is induced in a persistent manner that can be related in time to cell death. A transient increase in JNK activation has also been observed with other agents that either fail to induce or at least have a minimal e ect in cell death such as cytokines (Su et al, 1994;Chen et al, 1996a) and in our hands also trans-DDP. As previously described for gamma radiation (Chen et al, 1996a,b), oxidative stress (Mendelson et al, 1996) and high doses of U.V.C light (Chen et al, 1996b), cis-DDP induces a late and sustained activation of JNK activity that as with other types of stress, correlate with apoptosis.…”

Section: Cis-ddp Induces a Persistent Activation Of Jnk But Not Mapksupporting

confidence: 79%

Cisplatin induces a persistent activation of JNK that is related to cell death

1998

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Genotoxic stress triggers signalling pathways that either mediate cell killing or protection of a ected cells. While induction of p53 is observed for most of the genotoxins, activation of MAPK/SAPK cascades is not a general response. The role of MAPK/SAPK activation on cell fate, seems to be dependent, in some systems, on the balanced response among both cascades. We have here examined the e ect of cis and trans-DDP on the activation of ERK and JNK activities. While no signi®cant induction of ERK was observed with the compounds, both of them are able to strongly activate JNK. Trans-DDP response is rapid and transient while the cis-DDP one is slow and persistent. In contrast with the observed nuclear translocation of JNK in response to U.V. light, none of the platinum compounds induces translocation, on the contrary, activation of JNK occurs in both the nuclear and cytoplasmic compartments. Inhibition of tyrosine phosphatases by orthovanadate pretreatment prolongs the time of JNK induction in response to both platinum compounds. The positive modulation of JNK activation correlates with an increase in toxicity that, for cis-DDP corresponds to a tenfold decrease in the IC 50 . A strong increase in MKP-1 levels was observed only in response to trans-DDP suggesting the involvement of this activity in the downregulation of JNK activity in response to this compound. Altogether the results suggest that the prolonged activation of JNK in response to cis-DDP contributes to cell death induction.

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Section: Cis-ddp Induces a Persistent Activation Of Jnk But Not Mapksupporting

confidence: 79%

Cisplatin induces a persistent activation of JNK that is related to cell death

1998

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“…The lack of inhibition of the activation of the IL-2 and the NFAT promoter by the dominant negative mutant SEK1K299R suggests that the contribution of the SAPK pathway may not be critical for the activation of NFAT by Tpl-2. Alternatively, SAPK may be activated by pathways (Su et al, 1994) that are SEK1-independent. Activation of the NFAT-regulated minimal promoter in EL4 cells following transient transfection of activated Raf1 (Raf1Y340D) and activated calcineurin (DCnA) or activated NFATc provided support to this model.…”

Section: Discussionmentioning

confidence: 99%

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

1998

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The Tpl-2 kinase activates the nuclear factor of activated T cells (NFAT) and induces IL-2 expression in T-cell lines. Here we show that the activation of the IL-2 promoter by Tpl-2 is inhibited by mutant signaling molecules that inhibit the mitogen-activated protein kinase (MAPK) or the calcineurin/NFAT pathways and is promoted by combinations of signaling molecules that activate these pathways. We, therefore, conclude that signals generated by the convergence of the MAPK and the calcineurin/NFAT pathway are necessary and su cient for the activation of the IL-2 promoter by Tpl-2. The activation of both the IL-2 promoter and an NFAT-driven minimal promoter were shown to depend on signals transduced by Raf1. However, it was only the IL-2 promoter whose activation by Tpl-2 was fully blocked by the dominant negative mutant MEK1S218/ 222A and the MEK1/MEK2 inhibitor PD098059. Since the activation of NFAT is MAPK-dependent these ®ndings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2. In addition, they suggested that the activation of the IL-2 promoter is under the control of not only NFAT but also a second factor whose activation is MEK-dependent. Experiments in COS-1 and EL-4 cells con®rmed both hypotheses and revealed that the second factor activated by Tpl-2 is NF-kB. While the activation of the IL-2 promoter and an NFAT-driven minimal promoter by Tpl-2 was fully blocked by the dominant negative mutant NFATD418, it was only partially blocked by the calcineurin inhibitor cyclosporin A suggesting that the Tpl-2-mediated NFAT activation is under the control of a combination of calcineurindependent and independent pathways. Both pathways were fully blocked by Bcl-2 or Bcl-X L .

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“…Potential candidates could include the JNK/ SAPKs which not only activate Jun transactivation but also ATF-2 and ETS-family members Kyriakis et al, 1994;Minden et al, 1994;Sanchez et al, 1994;Su et al, 1994;Gupta et al, 1995). These protein kinases could potentially phosphorylate the Pro-Met-Ser-Pro motif in Stat3 and may be activated by many of the stimuli that can activate this transcription factor.…”

Section: Discussionmentioning

confidence: 99%

Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

et al. 1997

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The binding of insulin to its receptor initiates multiple signal transduction pathways regulating such diverse processes as proliferation, di erentiation, glucose transport, and glycogen metabolism. The STAT-family of transcription factors has been demonstrated to play a critical role in gene induction by a variety of hemopoietic cytokines and hormones. Furthermore, constitutive activation of STATs is observed in transformed cells. Here we describe activation of a transcriptional complex binding to a consensus STAT-transcriptional element in response to insulin challenge. This complex is induced rapidly after tyrosine autophosphorylation of the insulin receptor, and is sustained for several hours. Supershift analysis of the insulin-induced complex reveals that it speci®cally contains the transcription factor Stat3. DAN binding of this complex is inhibited by pre-incubation with tyrosine, but not serine/threonine protein kinase inhibitors, whereas transcriptional activation is inhibited by both. Utilising a dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3 DNAbinding and also transactivation do not require p21ras. Furthermore, although previous studies have suggested a role for MAP kinases (ERKs) and PI-3K in STAT activation, utilising the speci®c MEK inhibitor PD098059 and the PI-3K inhibitor wortmannin, we demonstrate that activation of ERKs or PI-3K are not required for insulin induced Stat3 phosphorylation or transactivation.

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JNK is involved in signal integration during costimulation of T lymphocytes

Cited by 864 publications

References 51 publications

Cisplatin induces a persistent activation of JNK that is related to cell death

Cisplatin induces a persistent activation of JNK that is related to cell death

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

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