Loss of TRB3 Alters Dynamics of MLK3-JNK Signaling and Inhibits Cytokine-activated Pancreatic Beta Cell Death

Humphrey, Rohan K.; Ray, Anamika; Gonuguntla, Sumati; Hao, Ergeng; Jhala, Ulupi S.

doi:10.1074/jbc.m114.575613

Cited by 13 publications

(25 citation statements)

References 57 publications

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“…In order to clarify the mechanism by which PRL modulates JNK, we assessed the role of AKT kinase in this context. The AKT pathway is an important antiapoptotic signal that inhibits the MAPK cascade involved in cytokine-induced JNK activation (Franke et al 1997, Humphrey et al 2014), and we have previously shown that PRL induces PI3K/AKT during pregnancy (Amaral et al 2004). We presently observed that PRL increases the phosphorylation of AKT and demonstrated that the inhibition of this AKT activation prevent PRL inhibitory effects and even increases cytokine-induced JNK activation.…”

Section: Discussionmentioning

confidence: 96%

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Prolactin protects against cytokine-induced beta-cell death by NFκB and JNK inhibition

Nardelli

Vanzela

Benedicto

et al. 2018

Journal of Molecular Endocrinology

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Type 1 diabetes is caused by an autoimmune assault that induces progressive beta-cell dysfunction and dead. Pro-inflammatory cytokines, such as interleukin 1 beta (IL1B), tumor necrosis factor (TNF) and interferon gamma (IFNG) contribute for beta-cell death, which involves the activation of the nuclear factor kappa B (NFκB) and c- Jun N-terminal kinase (JNK). Prolactin (PRL), a physiological mediator for beta-cell proliferation, was shown to protect beta cells against cytokines pro-apoptotic effects. We presently investigated the mechanisms involved in the protective effects of prolactin against cytokine-induced beta-cell death. The findings obtained indicate that STAT3 activation is involved in the anti-apoptotic role of PRL in rat beta cells. PRL prevents the activation of JNK via AKT and promotes a shift from expression of pro- to anti-apoptotic proteins downstream of the JNK cascade. Furthermore, PRL partially prevents the activation of NFκB and the transcription of its target genes ,, , A20 and and also decreases NO production. On the other hand, the pro-survival effects of PRL do not involve modulation of cytokine-induced endoplasmic reticulum stress. These results suggest that the beneficial effects of PRL in beta cells involve augmentation of anti-apoptotic mechanisms and, at the same time, reduction of pro-apoptotic effectors, rendering beta cells better prepared to deal with inflammatory insults. The better understanding of the pro-survival mechanisms modulated by PRL in beta cells can provide tools to prevent cell demise during an autoimmune attack or following islet transplantation.

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Section: Discussionmentioning

confidence: 96%

“…AKT is a modulator of JNK activation (Humphrey et al 2014). We next evaluated whether the observed decrease in cytokine-induced JNK phosphorylation, induced by PRL (Fig.…”

Section: Prl-decreased Jnk Activation Is Dependent Of Aktmentioning

confidence: 99%

Prolactin protects against cytokine-induced beta-cell death by NFκB and JNK inhibition

Nardelli

Vanzela

Benedicto

et al. 2018

Journal of Molecular Endocrinology

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“…We detected that MLK3 was expressed at a higher level in psoriatic tissues. MLK3 plays important roles not only in regulation of inflammatory mediator secretion by controlling the transcriptional activity of Janus kinase and NF‐κB, but also in the mitogen regulation of B‐Raf and extracellular signal‐related kinase . Silencing MLK3 in NHEKs significantly attenuated the cell proliferation and chemokine secretion promotion of the miR‐145‐5p inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR‐145‐5p contributes to hyperproliferation of keratinocytes and skin inflammation in psoriasis

Yan

Qiao

et al. 2018

Br J Dermatol

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Background The extensive involvement of microRNAs (miRNAs) in the pathogenesis of psoriasis is well documented. However, little is known about the contribution of specific miRNAs to the prevalence of this disease. Objectives To explore the role of miR-145-5p in psoriasis. Methods miRNA microarray analysis was performed in four patients with psoriasis and four controls. Quantitative reverse-transcriptase polymerase chain reaction and fluorescence in situ hybridization were used to identify the dysregulated miR-NAs. Luciferase assays were performed to determine whether miR-145-5p targets mixed-lineage kinase (MLK)3. CCK-8 assay and Magnetic Luminex Assay were performed to measure cell proliferation and chemokine secretion. Western blot analysis was used to investigate the protein levels of MLK3 and its downstream effectors. Mouse models of psoriasis were established for in vivo experiments.Results miR-145-5p was downregulated in psoriatic lesional skin. Luciferase assays showed that MLK3 is a direct target of miR-145-5p. Overexpression of miR-145-5p in normal human epidermal keratinocytes (NHEKs) suppressed cell proliferation and secretion of chemokines. In contrast, silencing miR-145-5p promoted NHEK proliferation and increased chemokine secretion. Silencing MLK3 abrogated miR-145-5p inhibitor-induced promotion of cell proliferation and chemokine expression. miR-145-5p regulates nuclear factor-jB and signal transducer and activator of transcription 3 by targeting MLK3. Delivery of agomiR-145-5p into the skin decreased epidermal hyperplasia and ameliorated psoriasis-like dermatitis. Delivery of antagomiR-145-5p led to the opposite effects. Conclusions Our findings indicate that miR-145-5p negatively regulates proliferation and chemokine secretion of NHEKs by targeting MLK3, and downregulation of miR-145-5p contributes to skin inflammation in psoriasis lesions. What's already known about this topic?• Psoriasis is a chronic, immune-mediated disease and has a strong genetic component.• Aberrant microRNA expression contributes to psoriasis development and progression.• miR-145-5p has been studied in immune-mediated disease, but not in psoriasis. What does this study add?• miR-145-5p plays important functions in psoriasis by targeting mixed-lineage kinase 3.• Downregulation of miR-145-5p promotes keratinocyte proliferation and exacerbates skin inflammation in psoriasis.

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“…17 Furthermore, Humphrey et al have demonstrated that TRB3 is required for optimal MLK3-JNK activation in pancreatic beta cells. 20 Adding SB203580 was demonstrated as enhancing the expression of TRB3 in response to 4-hydroxy-trans-2-nonenal (4-HNE) in PC12 cells. 21 Furthermore, Zhang et al indicated that TRB3 may be involved in diabetic nephropathy by regulating the collagen type IV through the ERK1e2 MAPK pathway.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin alleviates cardiomyocyte apoptosis by suppressing TRB3 induced by acute myocardial infarction and hypoxia

Cheng¹,

Wang³

et al. 2017

Journal of the Formosan Medical Association

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Background/Purpose: TRB3 (tribbles 3), an apoptosis-regulated gene, increases during endoplasmic reticulum stress. Hypoxia can induce inflammatory mediators and apoptosis in cardiomyocytes. However, the expression of TRB3 in cardiomyocyte apoptosis under hypoxia is not thoroughly known. We investigated the regulation mechanism of TRB3 expression and apoptosis induced by hypoxia in cardiomyocytes. Methods: An in vivo model of acute myocardial infarction (AMI) was applied in adult Wistar rats to induce myocardial hypoxia. Rat neonatal cardiomyocytes were subjected to 2.5% O 2 to induce hypoxia. Results: The expression of TRB3 was evaluated in cultured rat neonatal cardiomyocytes subjected to hypoxia. Hypoxia significantly enhanced TRB3 protein and mRNA expression. Adding c-jun N-terminal kinase (JNK) inhibitor SP600125, JNK small interfering RNA (siRNA), tumor necrosis factor-a (TNF-a) antibody, and atorvastatin 30 minutes before hypoxia reversed the induction of TRB3 protein. A gel-shift assay showed the DNA-binding activity of growth arrest and DNA damage-inducible gene 153 (GADD153), which increased after hypoxia. Hypoxia increased, whereas the TRB3-mut plasmid, SP600125, and TNF-a antibody abolished the hypoxia-induced TRB3 promoter activity. Hypoxia increased the secretion of TNF-a from cardiomyocytes. Exogenous administration of TNF-a recombinant protein to the cardiomyocytes without hypoxia increased TRB3 protein expression, similar to that observed after hypoxia. Hypoxia-induced cardiomyocyte apoptosis is inhibited by TRB3 siRNA, the TNF-a antibody, and atorvastatin. Atorvastatin reduced the TRB3 expression and cardiomyocyte apoptosis induced by AMI. Hypoxia induces TRB3 through TNF-a, JNK, and the GADD153 pathway. Conclusion: Treatment of atorvastatin inhibits the expression of TRB3 and cardiomyocyte apoptosis induced by AMI and hypoxia.

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Loss of TRB3 Alters Dynamics of MLK3-JNK Signaling and Inhibits Cytokine-activated Pancreatic Beta Cell Death

Abstract: Background: MLK3 induces TRB3 to inhibit AKT and compromise beta cell survival. Results: AKT regulates novel phosphorylation, ubiquitination, and degradation of MLK3, explaining why TRB3 Ϫ/Ϫ islets

Cited by 13 publications

References 57 publications

Prolactin protects against cytokine-induced beta-cell death by NFκB and JNK inhibition

Prolactin protects against cytokine-induced beta-cell death by NFκB and JNK inhibition

Downregulation of miR‐145‐5p contributes to hyperproliferation of keratinocytes and skin inflammation in psoriasis

Atorvastatin alleviates cardiomyocyte apoptosis by suppressing TRB3 induced by acute myocardial infarction and hypoxia

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