An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response

Brown, Max; Strudwick, Natalie; Suwara, Monika; Sutcliffe, Louise; Mihai, Adina D; Ali, Asma; Watson, Jamie N.; Schröder, Martin

doi:10.1242/jcs.179127

Cited by 70 publications

(60 citation statements)

References 127 publications

(163 reference statements)

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“…47,48 JNK activates JUN in response to stresses such as ultraviolet irradiation or inflammation whereas ERK activates JUN in response to growth factor stimulation 53 . JNK is a well-established target of IRE1α and promotes both survival and death in response to ER stress 54 . In response to chemically induced ER stress, we have observed that JUN is phosphorylated at Ser73, which is a known substrate of JNK.…”

Section: Discussionmentioning

confidence: 99%

JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia

et al. 2016

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The transcription factor JUN is frequently overexpressed in multiple genetic sub-types of acute myeloid leukemia (AML), however, the functional role of JUN in AML is not well defined. Here we report that shRNA-mediated inhibition of JUN decreases AML cell survival and propagation in vivo. By performing RNA-seq analysis, we discovered that JUN inhibition reduces the transcriptional output of the Unfolded Protein Response (UPR), an intracellular signaling transduction network activated by endoplasmic reticulum (ER) stress. Specifically, we found that JUN is activated by MEK signaling in response to ER stress and that JUN binds to the promoters of several key UPR effectors, such as XBP1 and ATF4, to activate their transcription and allow AML cells to properly negotiate ER stress. Additionally, we observed that shRNA-mediated inhibition of XBP1 or ATF4 induces AML cell apoptosis and significantly extends disease latency in vivo tying the reduced survival mediated by JUN inhibition to loss of pro-survival UPR signaling. These data uncover a previously unrecognized role of JUN as a regulator of the UPR as well as provide key new insights into the how ER stress responses contribute to AML and identify JUN and the UPR as promising therapeutic targets in this disease.

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Section: Discussionmentioning

confidence: 99%

JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia

et al. 2016

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“…The data presented here demonstrated that an ischaemic insult of 20 minutes in perfused rat hearts is sufficient to trigger the UPR. 30,33 The mechanisms involved in this pro-survival signalling response include the JNK-induced expression of anti-apoptotic genes 30 and the JNK-mediated induction of autophagic flux. Furthermore, IRE1α pathway could also be involved in elevation of both, JNK phosphorylation and cleavage of caspase-12.…”

Section: Discussionmentioning

confidence: 99%

“…The role of JNK activation in the ER stress response has also been reconsidered. [30][31][32] JNK signalling is currently accepted to have functionally distinct phases with opposing effects in the ER stress response. In contrast to the pro-apoptotic late phase, the early and transient phase of JNK activation has been reported to protect ER-stressed cells from executing apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the pro-apoptotic late phase, the early and transient phase of JNK activation has been reported to protect ER-stressed cells from executing apoptosis. 30,33 The mechanisms involved in this pro-survival signalling response include the JNK-induced expression of anti-apoptotic genes 30 and the JNK-mediated induction of autophagic flux. 31,32 Taken together, these reported results allow us to speculate that under the sub-cytotoxic ER stress induced by the stunned heart both, caspase-12 activation and JNK-phosphorylation, are either not playing any role in apoptosis or leading to protective cascades during the ER stress response.…”

Section: Discussionmentioning

confidence: 99%

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Chemical chaperones improve the functional recovery of stunned myocardium by attenuating the endoplasmic reticulum stress

et al. 2019

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Aim Myocardial ischaemia/reperfusion (I/R) produces structural and functional alterations depending on the duration of ischaemia. Brief ischaemia followed by reperfusion causes reversible contractile dysfunction (stunned heart) but long‐lasting ischaemia followed by reperfusion can result in irreversible injury with cell death. Events during I/R can alter endoplasmic reticulum (ER) function leading to the accumulation of unfolded/misfolded proteins. The resulting ER stress induces activation of several signal transduction pathways, known as unfolded protein response (UPR). Experimental evidence shows that UPR contributes to cell death in irreversible I/R injury; however, there is still uncertainty for its occurrence in the stunned myocardium. This study investigated the ER stress response and its functional impact on the post‐ischaemic cardiac performance of the stunned heart. Methods Perfused rat hearts were subjected to 20 minutes of ischaemia followed by 30 minutes of reperfusion. UPR markers were evaluated by qRT‐PCR and western blot. Post‐ischaemic mechanical recovery was measured in absence and presence of two chemical chaperones: tauroursodeoxycholic acid (TUDCA) and 4‐phenylbutyric acid (4‐PBA). Results Analysis of mRNA and protein levels of various ER stress effectors demonstrated that different UPR signalling cascades, involving both pro‐survival and pro‐apoptotic pathways, are activated. Inhibition of the UPR with chemical chaperones improved the post‐ischaemic recovery of cardiac mechanical function without affecting the I/R‐induced increase in oxidative stress. Conclusion Our results suggest that prevention of ER stress by chemical chaperones could be a therapeutic tool to limit deterioration of the contractile function in clinical settings in which the phenomenon of myocardial stunning is present.

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“…In humans, JNK activation has been linked to the upregulation of Manganese dependent-Super Oxide Dismutase (Mn-SOD) and catalases depending on the deacetylase SIRT1 and the FOXO transcription factor1364. In a more recent study, the early JNK response has been proposed to inhibit apoptosis67. Collectively, the results obtained in this study and other studies on various organisms suggest that the primary role of JNK signalling in thermal and solar spectrum UVR-induced oxidative stress consists of triggering a pro-survival anti-oxidant response.…”

Section: Discussionmentioning

confidence: 99%

The c-Jun N-terminal kinase prevents oxidative stress induced by UV and thermal stresses in corals and human cells

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Grover

et al. 2017

Sci Rep

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Coral reefs are of major ecological and socio-economic interest. They are threatened by global warming and natural pressures such as solar ultraviolet radiation. While great efforts have been made to understand the physiological response of corals to these stresses, the signalling pathways involved in the immediate cellular response exhibited by corals remain largely unknown. Here, we demonstrate that c-Jun N-terminal kinase (JNK) activation is involved in the early response of corals to thermal and UV stress. Furthermore, we found that JNK activity is required to repress stress-induced reactive oxygen species (ROS) accumulation in both the coral Stylophora pistillata and human skin cells. We also show that inhibiting JNK activation under stress conditions leads to ROS accumulation, subsequent coral bleaching and cell death. Taken together, our results suggest that an ancestral response, involving the JNK pathway, is remarkably conserved from corals to human, protecting cells from the adverse environmental effects.

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An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response

Cited by 70 publications

References 127 publications

JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia

JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia

Chemical chaperones improve the functional recovery of stunned myocardium by attenuating the endoplasmic reticulum stress

The c-Jun N-terminal kinase prevents oxidative stress induced by UV and thermal stresses in corals and human cells

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