Activation of Ets‐2 by oxidative stress induces Bcl‐xL expression and accounts for glial survival in amyotrophic lateral sclerosis

Lee, Junghee; Kannagi, Mari; Ferrante, Robert J.; Kowall, Neil W.; Ryu, Hoon

doi:10.1096/fj.08-121046

Cited by 38 publications

(33 citation statements)

References 33 publications

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“…Overexpression of TDP-43 Down-regulated Bcl-xL ExpressionEarlier studies have shown that Bcl-xL expression is reduced in motor neurons of mouse models of ALS and in human ALS cases (29,30). In accordance, Bcl-xL expression was reduced by overexpression of TDP-43 (Fig.…”

Section: Tdp-43-induced Death Is Associated With Increase Of Bim Exprmentioning

confidence: 56%

“…Bcl-xL and Bcl-2 were reduced in brain areas where motor neuron death occurred in ALS model mice (29). Bcl-xL expression was found to be reduced in motor neurons of human ALS cases (30). These findings together suggest that the abnormal regulation of Bcl-2-related proteins may be responsible for the progression of motor neuron death in ALS.…”

Section: Tdp-43 Cleavage Leads To the Attenuation Of Tdp-43-inducedmentioning

confidence: 80%

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TDP-43-induced Death Is Associated with Altered Regulation of BIM and Bcl-xL and Attenuated by Caspase-mediated TDP-43 Cleavage

Suzuki

Lee

Matsuoka

2011

Journal of Biological Chemistry

103

110

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FTLD-U is the most common variant of FTLD. FTLD, a heterogeneous syndrome characterized by progressive dementia, is caused by degeneration of the frontal and anterior temporal lobes, and is a leading cause of dementia in patients presenting before the age of 65 years (5). The pathogenesis of FTLD remains unknown. ALS is the most common motor neuron disease, characterized by progressive loss of motor neurons (6, 7). The pathogenesis of ALS remains undetermined although various hypotheses have been proposed: e.g. misfolded protein aggregates, mitochondrial dysfunction, glutamate toxicity, oxidative stress, disturbance of intracellular trafficking, and ER stress (8). About 10% of ALS cases occur in a genetically inherited manner.Post-translational modifications of TDP-43 including truncation, hyperphosphorylation, and ubiquitination are assumed to be linked to abnormal aggregation (1, 2). In particular, C-terminal fragments (CTFs) of TDP-43 are prone to form cytoplasmic aggregates (9 -11). Although it is apparent that cytoplasmic aggregates of TDP-43 are closely related to the pathogenesis of FTLD-U and ALS, it remains unknown how CTFs are generated and whether the aggregate formation of TDP-43 is a cause or a result of neuronal toxicity.Caspase activation has been observed in motor neurons of ALS (12-15) and neurons in FTLD patients (16). One possible mechanism underlying the generation of CTFs is the cleavage of TDP-43 by activated caspases. In reality, multiple studies have shown that TDP-43 is cleaved in a caspase-dependent manner and the resulting CTFs of TDP-43 are constituents in the inclusion bodies (17)(18)(19).Some clinical studies have suggested that the levels of TDP-43 are up-regulated in motor neurons of sporadic ALS patients, based on the finding that the levels of TDP-43 are up-regulated in cerebrospinal fluids (20)

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Section: Tdp-43-induced Death Is Associated With Increase Of Bim Exprmentioning

confidence: 56%

Section: Tdp-43 Cleavage Leads To the Attenuation Of Tdp-43-inducedmentioning

confidence: 80%

TDP-43-induced Death Is Associated with Altered Regulation of BIM and Bcl-xL and Attenuated by Caspase-mediated TDP-43 Cleavage

Suzuki

Lee

Matsuoka

2011

Journal of Biological Chemistry

103

110

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“…In the majority of our cultures, GICs containing a downregulated NFkB pathway tend to differentiate toward a neuronal phenotype, which might reflect the need of NFkB-dependent survival factors by astrocytes. In line with this, Bcl-x L , an antiapoptotic NFkB target gene, contributes to the survival of primary astrocytes in culture (Lee et al, 2009), and it has been suggested that inhibition of the NFkB pathway blocks astroglial differentiation from mesencephalic neural precursors (Sabolek et al, 2006). However, tumor cells obtained from xenografted mice only showed a tendential, but not significant, pattern of neuronal differentiation after treatment with the NFkB activation inhibitor.…”

Section: Discussionmentioning

confidence: 95%

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

et al. 2011

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Glioblastoma multiforme is one of the most devastating cancers and presents unique challenges to therapy because of its aggressive behavior. Cancer-initiating or progenitor cells have been described to be the only cell population with tumorigenic capacity in glioblastoma. Therefore, effective therapeutic strategies targeting these cells or the early precursors may be beneficial. We have established different cultures of glioblastoma-initiating cells (GICs) derived from surgical specimens and found that, after induction of differentiation, the NFjB transcriptional pathway was activated, as determined by analyzing key proteins such as p65 and IjB and the upregulation of a number of target genes. We also showed that blockade of nuclear factor (NF)jB signaling in differentiating GICs by different genetic strategies or treatment with smallmolecule inhibitors, promoted replication arrest and senescence. This effect was partly mediated by reduced levels of the NFjB target gene cyclin D1, because its downregulation by RNA interference reproduced a similar phenotype. Furthermore, these results were confirmed in a xenograft model. Intravenous treatment of immunodeficient mice bearing human GIC-derived tumors with a novel smallmolecule inhibitor of the NFjB pathway induced senescence of tumor cells but no ultrastructural alterations of the brain parenchyma were detected. These findings reveal that activation of NFjB may keep differentiating GICs from acquiring a mature postmitotic phenotype, thus allowing cell proliferation, and support the rationale for therapeutic strategies aimed to promote premature senescence of differentiating GICs by blocking key factors within the NFjB pathway.

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“…Our study shows that astrocyte survival is correlated with the elevation of Ets-2 transcription factor and with Bcl-xL expression [39]. The transcriptional activation of Bcl-xL by Ets-2 compensates oxidative stress by preventing astrocytes from apoptotic or necrotic cell death during the pathogenesis of ALS.…”

Section: How Are Astrocytes Adapted To Environmental Stresses and Whamentioning

confidence: 99%

Astrocytes and Microglia as Non-cell Autonomous Players in the Pathogenesis of ALS

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that leads to a progressive muscle wasting and paralysis. The pathological phenotypes are featured by severe motor neuron death and glial activation in the lumbar spinal cord. Proposed ALS pathogenic mechanisms include glutamate cytotoxicity, inflammatory pathway, oxidative stress, and protein aggregation. However, the exact mechanisms of ALS pathogenesis are not fully understood yet. Recently, a growing body of evidence provides a novel insight on the importance of glial cells in relation to the motor neuronal damage via the non-cell autonomous pathway. Accordingly, the aim of the current paper is to overview the role of astrocytes and microglia in the pathogenesis of ALS and to better understand the disease mechanism of ALS.

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Activation of Ets‐2 by oxidative stress induces Bcl‐xL expression and accounts for glial survival in amyotrophic lateral sclerosis

Cited by 38 publications

References 33 publications

TDP-43-induced Death Is Associated with Altered Regulation of BIM and Bcl-xL and Attenuated by Caspase-mediated TDP-43 Cleavage

TDP-43-induced Death Is Associated with Altered Regulation of BIM and Bcl-xL and Attenuated by Caspase-mediated TDP-43 Cleavage

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

Astrocytes and Microglia as Non-cell Autonomous Players in the Pathogenesis of ALS

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