A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

Zareen, Neela; Biswas, Subhas C.; Greene, Lloyd A.

doi:10.1038/cdd.2013.128

Cited by 42 publications

(45 citation statements)

References 59 publications

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“…It is worth noting that it has been reported that TRIB3-null animals show upregulation of TRIB1 and TRIB2 in at least some tissues. 39 As TRIB2 is associated with induction of acute myelogenous leukemia 40,41 and TRIB1 with other malignancies, 42,43 changes in the levels of the other Tribbles isoforms may also contribute to the phenotype observed in Trib3 À / À animals.…”

Section: Discussionmentioning

confidence: 99%

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

et al. 2014

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Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumorsuppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis. Pseudokinases constitute a group of proteins that have a kinase-like domain that lacks at least one of the conserved catalytic residues. 1,2 Different studies have shown that some pseudokinases can exhibit low levels of kinase activity, while others have critical roles as activators of their specific targets. 1,2 Moreover, aberrant regulation of pseudokinases has been implicated in the etiology and progression of a variety of diseases, including cancer. 3 The Tribbles family of pseudokinases was first described in Drosophila as a negative regulator of cell division in early embryogenesis. [4][5][6][7] There are three mammalian Tribbles isoforms (Trib1, Trib2 and Trib3), homologs to the Drosophila tribbles proteins, and they all share a highly conserved central kinase-like domain, which lacks catalytic residues, and a 'tribbles specific' C-terminal domain, which has been proposed to participate in the binding to different Tribbles partners. 8 Tribbles pseudokinase-3 (TRIB3; also named TRB3, NIPK and SKIP3) has been proposed to interact with several proteins, including the transcription factors activating transcription factor 4 (ATF-4) and CHOP 9 as well as with several MAPKs. 10 TRIB3 has also been shown to interact and inhibit AKT, 11 which has been suggested to suppress insulin signaling. 11,12 In addition, administration of different anticancer agents promotes cancer cell death via TRIB3 upregulation and the subsequent inhibition of Akt. [13][14][15][16][17][18][19] However, the precise molecular basis of the regulation of Akt by TRIB3 and whether loss of this pseudokinase may contribute to cancer initiation and progression remains to be clarified.In this study, we investigated the effect of the genetic inactivation of TRIB3 in several cellular and animal models of cancer. Our findings indicate that genetic inhibition of TRIB3 enhances tumorigenesis and that this effect is due -at least primarily -to a selective inactivation of the transcription factor FOXO by the mammalian target of rapamycin complex 2 (mTORC2)/AKT axis. ResultsGenetic inhibition of TRIB3 facilitates oncogene transformation and enhances the tumorigenicity of cancer c...

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Section: Discussionmentioning

confidence: 99%

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

et al. 2014

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“…16 A self-amplifying feedforward loop exists between Akt dephosphorylation/inactivation and FoxO dephosphorylation/activation and involves Trib3, a FoxO-induced molecule that interferes with Akt phosphorylation, thus leading to progressive FoxO activation and neuronal death. 17 In the etoposide-induced apoptosis model, Akt was rapidly decreased (at both mRNA and protein levels). Importantly, we detected increased levels of miR-711 and Akt mRNA in the RISC complex.…”

Section: Mir-711 Activates Neuronal Apoptosis B Sabirzhanov Et Almentioning

confidence: 99%

“…13,14 In contrast, Akt (protein kinase B) promotes neuronal survival by phosphorylating/inactivating pro-apoptotic proteins such as forkhead transcription factor FoxO3 and GSK3β that are important initiators of BH3-only protein expression. [15][16][17] Akt pathway inhibition leads to dephosphorylation/activation of FoxO3a and induction of its pro-apoptotic target genes including PUMA and Bim. 18,19 The present study tested the hypothesis that TBI-induced changes of selected miRs can initiate cell death pathways that result in neuronal loss and neurological deficits.…”

mentioning

confidence: 99%

miR-711 upregulation induces neuronal cell death after traumatic brain injury

et al. 2015

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Traumatic brain injury (TBI) is a leading cause of mortality and disability. MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression at post-transcriptional level and may be key modulators of neuronal apoptosis, yet their role in secondary injury after TBI remains largely unexplored. Changes in miRs after controlled cortical impact (CCI) in mice were examined during the first 72 h using miR arrays and qPCR. One selected miR (711) was examined with regard to its regulation and relation to cell death; effects of miR-711 modulation were evaluated after CCI and using in vitro cell death models of primary cortical neurons. Levels of miR-711 were increased in the cortex early after TBI and in vitro models through rapid upregulation of miR-711 transcription (pri-miR-711) rather than catabolism. Increases coincided with downregulation of the pro-survival protein Akt, a predicted target of miR-711, with sequential activation of forkhead box O3 (FoxO3)a/glycogen synthase kinase 3 (GSK3)α/β, pro-apoptotic BH3-only molecules PUMA (Bcl2-binding component 3) and Bim (Bcl2-like 11 (apoptosis facilitator)), and mitochondrial release of cytochrome c and AIF. miR-711 and Akt (mRNA) co-immunoprecipitated with the RNA-induced silencing complex (RISC). A miR-711 hairpin inhibitor attenuated the apoptotic mechanisms and decreased neuronal death in an Aktdependent manner. Conversely, a miR-711 mimic enhanced neuronal apoptosis. Central administration of the miR-711 hairpin inhibitor after TBI increased Akt expression and attenuated apoptotic pathways. Treatment reduced cortical lesion volume, neuronal cell loss in cortex and hippocampus, and long-term neurological dysfunction. miR-711 changes contribute to neuronal cell death after TBI, in part by inhibiting Akt, and may serve as a novel therapeutic target.

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“…It was identified as a novel ER stress-inducible gene that, when up-regulated, activated several genes involved in cell death during ER stress (21). Trib3 is also shown to be elevated by several stresses, including hypoxia, 6-hydroxydopamine, growth factor deprivation, anoxia, and ethanol exposure (16,(22)(23)(24)(25)(26)(27)(28). It has also been shown that Trib3 is elevated in Parkinson's disease brains and mediates neuron death in various Parkinson's disease models (27).…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

“…We interfered with the expression of Trib3 using previously described shRNA constructs (23). The Trib3 shRNA construct efficiently blocked induction of Trib3 by A␤ in neuronally differentiated (primed) PC12 cells (Fig.…”

Section: A␤ Treatment Induces Trib3 Mrna and Protein Levels Inmentioning

confidence: 99%

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

Saleem

Biswas

2017

Journal of Biological Chemistry

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Edited by Paul E. FraserAmyloid-␤ (A␤)-induced neuron death is considered central to the pathogenesis of Alzheimer's disease (AD). Among several death modalities, autophagy and apoptosis play important roles in A␤-induced neuron death suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon A␤ treatment, tribbles pseudokinase 3 (Trib3, an ortholog of Drosophila Tribbles) is up-regulated in neurons both in vivo and in vitro. Increased Trib3 levels inhibited the activity of the kinase Akt by interacting with it. As a result, forkhead box O1 (FoxO1), a transcription factor that is negatively regulated by Akt, was activated, translocated to the nucleus, and induced the pro-apoptotic gene BCL2-like 11 (Bim). Conversely, FoxO1 responded to A␤ insult by binding to the Trib3 gene promoter, enhancing its expression. Our investigations further revealed that Trib3 also induces autophagy. We found that Trib3 indirectly activates unc-51-like autophagy-activating kinase1 (Ulk1) by impeding phosphorylation of, and thus inactivating, a negative regulator of Ulk1, mechanistic target of rapamycin. Ulk1 activation augmented autophagosome formation and reduced autophagy flux. Thus, Trib3 was required for formation of autophagosomes, which accumulated in neurons as autophagic flux was thwarted. Most importantly, silencing endogenous Trib3 strongly protected neurons from A␤ insult. Our results suggest that a self-amplifying feed-forward loop among Trib3, Akt, and FoxO1 in A␤-treated neurons induces both apoptosis and autophagy, culminating in neuron death. Thus, Trib3 may serve as a potential therapeutic target for AD.

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A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

Cited by 42 publications

References 59 publications

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

miR-711 upregulation induces neuronal cell death after traumatic brain injury

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

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