Amyotrophic Lateral Sclerosis-linked Mutant SOD1 Sequesters Hu Antigen R (HuR) and TIA-1-related Protein (TIAR)

Liang, Lu; Wang, Shuying; Zheng, Lei; Li, Xuelin; Suswam, Esther A.; Zhang, Xiaowen; Wheeler, Crystal G.; Nabors, L. Burt; Filippova, Natalia; King, Peter H.

doi:10.1074/jbc.m109.067918

Cited by 56 publications

(35 citation statements)

References 43 publications

(52 reference statements)

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“…Cells were washed with PBS with cycloheximide (100mg/ml) and trypsinized with 0.25%Trypsin/2.21mM EDTA and washed with ice-cold 1× PBS containing cycloheximide (100mg/ml) and pelleted. Protein collection, fractionation by sucrose gradient, RNA isolation and analysis are as previously described (29). …”

Section: Methodsmentioning

confidence: 99%

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The RNA-Binding Protein HuR Promotes Glioma Growth and Treatment Resistance

Filippova

Yang

Wang

et al. 2011

Molecular Cancer Research

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Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. We previously found that the mRNA binding protein, ELAV 1 (HuR), is upregulated in primary brain tumors and stabilizes growth factor mRNAs such as VEGF and IL-8. To better understand the role of HuR in brain tumor growth, we altered levels of HuR in glioma cells by shRNA or ectopic expression and measured tumor cell phenotype using in vitro and in vivo models. In HuR-silenced cells, we found a significant decrease in anchorage-independent growth and cell proliferation with a concomitant induction of apoptosis. Using an intracranial tumor model with primary glioblastoma cells, HuR silencing produced a significant decrease in tumor volume. In contrast, overexpression of HuR produced in vitro chemoresistance to standard glioma therapies. Since bcl-2 is abundantly expressed in glioma and associated with tumor growth and survival, we determined the impact of HuR on its regulation as a molecular validation to the cellular and animal studies. Using UV crosslinking and RNA immunoprecipitation, we show that HuR bound to the 3' untranslated region of all bcl-2 family members. Silencing of HuR led to transcript destabilization and reduced protein expression. Polysome profiling indicated loss of HuR from the translational apparatus. In summary, these findings reveal a HuR-dependent mechanism for cancer cell survival and sensitivity to chemotherapeutic drugs suggesting that HuR should be considered as a new therapeutic target.

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Section: Methodsmentioning

confidence: 99%

“…The control pLVTHM plasmid was obtained from Addgene, plasmid # 12247. Viral particles were packaged by as previously described (29). A total of 10 6 U251 cells were infected with 2 ml of viral supernatant in the final volume of 4 mL.…”

Section: Methodsmentioning

confidence: 99%

The RNA-Binding Protein HuR Promotes Glioma Growth and Treatment Resistance

Filippova

Yang

Wang

et al. 2011

Molecular Cancer Research

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133

123

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“…For RNA immunoprecipitation, WT astrocytes were treated with lipopolysaccharide (LPS) at 1 μg/ml or vehicle for 24 h, and cytoplasmic extracts were harvested using NE-PER (Pierce Endogen). Two hundred micrograms of extract were immunoprecipitated as described elsewhere (Lu et al, 2009). RNA was extracted from the precipitate and subjected to qRT-PCR.…”

Section: Methodsmentioning

confidence: 99%

KSRP: A checkpoint for inflammatory cytokine production in astrocytes

Lin

Chen

et al. 2012

Glia

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Chronic inflammation in the central nervous system (CNS) is a central feature of many neurodegenerative and autoimmune diseases. As an immunologically competent cell, the astrocyte plays an important role in CNS inflammation. It is capable of expressing a number of cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) that promote inflammation directly and through the recruitment of immune cells. Checkpoints are therefore in place to keep tight control over cytokine production. Adenylate/uridylate-rich elements (ARE) in the 3′ untranslated region of cytokine mRNAs serve as a major checkpoint by regulating mRNA stability and translational efficiency. Here, we examined the impact of KH-type splicing regulatory protein (KSRP), an RNA binding protein which destabilizes mRNAs via the ARE, on cytokine expression and paracrine phenotypes of primary astrocytes. We identified a network of inflammatory mediators, including TNF-α and IL-1β, whose expression increased 2 to 4-fold at the RNA level in astrocytes isolated from KSRP−/− mice compared to littermate controls. Upon activation, KSRP−/− astrocytes produced TNF-α and IL-1β at levels that exceeded control cells by 15-fold or more. Conditioned media from KSRP−/− astrocytes induced chemotaxis and neuronal cell death in vitro. Surprisingly, we observed a prolongation of half-life in only a subset of mRNA targets and only after selective astrocyte activation. Luciferase reporter studies indicated that KSRP regulates cytokine gene expression at both transcriptional and post-transcriptional levels. Our results outline a critical role for KSRP in regulating pro-inflammatory mediators and have implications for a wide range of CNS inflammatory and autoimmune diseases.

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“…On the other hand, we found that HuR-expressing cells are more efficient energy producers than corresponding control cells. Recent studies with mouse models have begun to link HuR to mitochondrion-regulated processes (59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

Carrascoso

Alcalde

Sánchez-Jiménez

et al. 2017

Molecular and Cellular Biology

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Mitochondria undergo frequent morphological changes to control their function. We show here that T-cell intracellular antigens (TIA1b/TIARb) and Hu antigen R (HuR) have antagonistic roles in mitochondrial function by modulating the expression of mitochondrial shaping proteins. Expression of TIA1b/TIARb alters the mitochondrial dynamic network by enhancing fission and clustering, which is accompanied by a decrease in respiration. In contrast, HuR expression promotes fusion and cristae remodeling and increases respiratory activity. Mechanistically, TIA proteins downregulate the expression of optic atrophy 1 (OPA1) protein via switching of the splicing patterns of OPA1 to facilitate the production of OPA1 variant 5 (OPA1v5). Conversely, HuR enhances the expression of OPA1 mRNA isoforms through increasing steady-state levels and targeting translational efficiency at the 3= untranslated region. Knockdown of TIA1/ TIAR or HuR partially reversed the expression profile of OPA1, whereas knockdown of OPA1 or overexpression of OPA1v5 provoked mitochondrial clustering. Middle-term expression of TIA1b/TIARb triggers reactive oxygen species production and mitochondrial DNA damage, which is accompanied by mitophagy, autophagy, and apoptosis. In contrast, HuR expression promotes mitochondrion-dependent cell proliferation. Collectively, these results provide molecular insights into the antagonistic functions of TIA1b/TIARb and HuR in mitochondrial activity dynamics and suggest that their balance might contribute to mitochondrial physiopathology.

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Amyotrophic Lateral Sclerosis-linked Mutant SOD1 Sequesters Hu Antigen R (HuR) and TIA-1-related Protein (TIAR)

Cited by 56 publications

References 43 publications

The RNA-Binding Protein HuR Promotes Glioma Growth and Treatment Resistance

The RNA-Binding Protein HuR Promotes Glioma Growth and Treatment Resistance

KSRP: A checkpoint for inflammatory cytokine production in astrocytes

T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

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