JNK-signaling: A multiplexing hub in programmed cell death

Dhanasekaran, Danny N.; Reddy, E. Premkumar

doi:10.18632/genesandcancer.155

Cited by 302 publications

(212 citation statements)

References 113 publications

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“…Systemic FAK14 did not induce any obvious deficits in mice and is well tolerated in clinical trials for cancer. JNK might be a better target than FAK because it can be pro-apoptotic (Dhanasekaran and Reddy 2017) but systemic JNK inhibition remains to be tested.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

Jia

Keasey

Lovins

et al. 2018

Glia

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Astrocyte-derived ciliary neurotrophic factor (CNTF) promotes adult subventricular zone (SVZ) neurogenesis. We found that focal adhesion kinase (FAK) and JNK, but not ERK or P38, repress CNTF in vitro. Here, we defined the FAK-JNK pathway and its regulation of CNTF in mice, and the related leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), which promote stem cell renewal at the expense of neurogenesis. Intrastriatal injection of FAK inhibitor, FAK14, in adult male C57BL/6 mice reduced pJNK and increased CNTF expression in the SVZ-containing periventricular region. Injection of a JNK inhibitor increased CNTF without affecting LIF and IL-6, and increased SVZ proliferation and neuroblast formation. The JNK inhibitor had no effect in CNTF−/− mice, suggesting that JNK inhibits SVZ neurogenesis by repressing CNTF. Inducible deletion of FAK in astrocytes increased SVZ CNTF and neurogenesis, but not LIF and IL-6. Intrastriatal injection of inhibitors suggested that P38 reduces LIF and IL-6 expression, whereas ERK induces CNTF and LIF. Intrastriatal FAK inhibition increased LIF, possibly through ERK, and IL-6 through another pathway that does not involve P38. Systemic injection of FAK14 also inhibited JNK while increasing CNTF, but did not affect P38 and ERK activation, or LIF and IL-6 expression. Importantly, systemic FAK14 increased SVZ neurogenesis in wildtype C57BL/6 and CNTF+/+ mice, but not in CNTF−/− littermates, indicating that it acts by upregulating CNTF. These data show a surprising differential regulation of related cytokines and identify the FAK-JNK-CNTF pathway as a specific target in astrocytes to promote neurogenesis and possibly neuroprotection in neurological disorders.

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Section: Discussionmentioning

confidence: 99%

Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

Jia

Keasey

Lovins

et al. 2018

Glia

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“…JNK/AP1 pathway is a key regulator of many cellular events, including cell death. [36][37][38][39][40][41][42][43] JNK/AP1 has pro-or anti-apoptotic functions, depending on cell type, nature of the death stimulus, duration of its activation and the activity of other signaling pathways. Studies have shown that in response to chronic stress, JNK/ AP1 activates the apoptosis pathway in order to eliminate the stressed cells.…”

Section: Discussionmentioning

confidence: 99%

The stress-activated protein kinase pathway and the expression of stanniocalcin-1 are regulated by miR-146b-5p in papillary thyroid carcinogenesis

Al-Abdallah

Jahanbani

Mehdawi

et al. 2020

Cancer Biology & Therapy

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Papillary thyroid cancer (PTC) is the most common type of thyroid cancer. Deciphering the pathophysiological mechanisms that contribute to PTC development is essential to the discovery of optimal diagnostic and therapeutic approaches. MiR-146b-5p has been identified as a cancer-associated microRNA highly up-regulated in PTC. This study explores the hypothesis that miR-146b-5p contributes to papillary thyroid carcinogenesis through regulation of cell signaling pathways in a manner that overcomes the cellular growth suppressive events and provides survival advantage. The effect of miR-146b-5p inhibition on major cancer related signaling pathways and expression of Stanniocalcin-1 (STC1), an emerging molecule associated with stress response and carcinogenesis, was tested in cultured primary thyroid cells using luciferase reporter assays, quantitative real-time PCR, immunofluorescence staining, and flow cytometry. Our results demonstrated that miR-146b-5p inhibits the JNK/AP1 pathway activity and down-regulates the expression of STC-1 in thyroid-cultured cells and in thyroid tissue samples. In the presence of miR-146b-5p, PTC cells were resistant to cell death in response to oxidative stress. This is a novel report that miR-146b-5p directly targets STC1 and regulates the activity of JNK/AP1 pathway. Considering the importance of the JNK/AP1 pathway and STC1 in mediating many physiological and pathological processes like apoptosis, stress response and cellular metabolism, a biological regulator of these pathways would have a great scientific and clinical significance. ARTICLE HISTORY

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“…JNK promotes apoptosis by several signalling pathways that were characterised in different cell experimental models. It is unlikely that all of the observed JNK's pro-apoptotic effects are present in all of the cells at the same time [120]. However, it is important to be aware of the JNK's ability to modulate apoptosis at different levels.…”

Section: Examples Of Signalling Molecules That Regulate Crosstalk Amomentioning

confidence: 99%

“…Activation of tumour necrosis factor receptor superfamily (e.g. TLRs or TNFαR) or DNA damage can trigger necroptosis by activation of the Complex I-IIa-IIbphosphorylated pseudokinase mixed lineage kinase domain-like protein (MLKL) signalling pathway; the final steps are (a) RIP3-dependent phosphorylation of MITO proteins PGAM5 and Drp-1 (increasing MITO ROS production); (b) insertion of phosphorylated MLKL into the MITO membrane with the cumulative effects of increased MITO membrane permeability, loss of membrane potential, decreased ATP and increased ROS production [120,[167][168][169]; and (c) phosphorylated MLKL's translocation to the plasma membrane and activation of Ca 2+ influx through plasma membrane channels with concomitant plasma membrane breakdown [169]. Increased cytosolic ROS production inactivates MAP kinase phosphatase 1, enabling sustained activation of phosphorylated JNK; phosphorylated JNK promotes necroptosis by (a) stimulating MLKL phosphorylation and by (b) promoting cytochrome c release from MITO via activation of BID [170,171].…”

Section: Examples Of Signalling Molecules That Regulate Crosstalk Amomentioning

confidence: 99%

Autophagy and Cell Death in Alzheimer’s, Parkinson’s and Prion Diseases

Ribarič¹,

Ribarič²

2020

Programmed Cell Death

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Neurodegenerative brain disorders (NBD) impair brain cells' proteostasis with the accumulation of normal, mutant, misfolded or unfolded proteins in the endoplasmic reticulum (ER). The increased ER burden of these proteins elicits the unfolded protein response (UPR) and stimulates autophagy (AUT). In the short term, UPR and AUT attenuate ER's burden. With prolonged ER stress, the UPR changes from supporting cell survival to promoting apoptosis. The failure of the UPR, to meet the increased protein burden, leads to an increase in cytosolic protein accumulation that initially further stimulates AUT. Over time, the accumulated proteins in the cytosol undergo post-translational changes into toxic monomers and oligomers that repress AUT at multiple levels and promote cell death. This review describes the interlinked signalling pathways of AUT, apoptosis and necroptosis and their modulation by Alzheimer's, Parkinson's and prion diseases and outlines the pharmacological strategies for targeting AUT, apoptosis and necroptosis signalling pathways. 2 oligomers; their production is stimulated by chronic inflammation and increased reactive oxygen species (ROS) production. These monomers and oligomers repress AUT and trigger either apoptosis or necroptosis (Figure 1) [4, 6-8]. Autophagy changes in selected NBDAn efficient autophagy (AUT) delays or attenuates the progression of AD, PD and PrD [9][10][11][12]. A summary of AUT changes in selected NBD is shown in Figure 2. Post-translationally modified proteins (PTMP)-such as soluble amyloid β-peptide 42 with a single oxidised methionine residue at position 35 (Aβ42-MET35-OX) in Alzheimer's disease, alpha-synuclein oxidised on methionine residues (MET-OX-αSYN) in Parkinson's disease and oxidised, self-propagating infectious isoforms of prion protein (MET-OX-PRP Sc ) in prion diseases (PrD)-inhibit (a) AUT, in AD, PD and PrD, and also (b) mitochondrial (MITO) function [13-23]. MET-OX-PRP Sc indirectly damage MITO function. The normal prion protein (PrP c ) binds with

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JNK-signaling: A multiplexing hub in programmed cell death

Cited by 302 publications

References 113 publications

Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

The stress-activated protein kinase pathway and the expression of stanniocalcin-1 are regulated by miR-146b-5p in papillary thyroid carcinogenesis

Autophagy and Cell Death in Alzheimer’s, Parkinson’s and Prion Diseases

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