scholarly journals Translating the Hypoxic Response—the Role of HIF Protein Translation in the Cellular Response to Low Oxygen

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 114 ◽  
Author(s):  
Iglika G. Ivanova ◽  
Catherine V. Park ◽  
Niall S. Kenneth
Keyword(s):  
Cellular Response ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Translation ◽  
Low Oxygen ◽  
Translation Rate ◽  
Hypoxic Response ◽  
Oxygen Sensitive ◽  
Multicellular Organisms

Hypoxia-Inducible Factors (HIFs) play essential roles in the physiological response to low oxygen in all multicellular organisms, while their deregulation is associated with human diseases. HIF levels and activity are primarily controlled by the availability of the oxygen-sensitive HIFα subunits, which is mediated by rapid alterations to the rates of HIFα protein production and degradation. While the pathways that control HIFα degradation are understood in great detail, much less is known about the targeted control of HIFα protein synthesis and what role this has in controlling HIF activity during the hypoxic response. This review will focus on the signalling pathways and RNA binding proteins that modulate HIFα mRNA half-life and/or translation rate, and their contribution to hypoxia-associated diseases.

The Therapeutic Potential and Role of miRNA, lncRNA, and circRNA in Osteoarthritis

2019 ◽  
Vol 19 (4) ◽  
pp. 255-263 ◽  
Author(s):  
Yuangang Wu ◽  
Xiaoxi Lu ◽  
Bin Shen ◽  
Yi Zeng
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Extracellular Matrix ◽  
Inflammatory Reaction ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Translation ◽  
Cochrane Library

Background: Osteoarthritis (OA) is a disease characterized by progressive degeneration, joint hyperplasia, narrowing of joint spaces, and extracellular matrix metabolism. Recent studies have shown that the pathogenesis of OA may be related to non-coding RNA, and its pathological mechanism may be an effective way to reduce OA. Objective: The purpose of this review was to investigate the recent progress of miRNA, long noncoding RNA (lncRNA) and circular RNA (circRNA) in gene therapy of OA, discussing the effects of this RNA on gene expression, inflammatory reaction, apoptosis and extracellular matrix in OA. Methods: The following electronic databases were searched, including PubMed, EMBASE, Web of Science, and the Cochrane Library, for published studies involving the miRNA, lncRNA, and circRNA in OA. The outcomes included the gene expression, inflammatory reaction, apoptosis, and extracellular matrix. Results and Discussion: With the development of technology, miRNA, lncRNA, and circRNA have been found in many diseases. More importantly, recent studies have found that RNA interacts with RNA-binding proteins to regulate gene transcription and protein translation, and is involved in various pathological processes of OA, thus becoming a potential therapy for OA. Conclusion: In this paper, we briefly introduced the role of miRNA, lncRNA, and circRNA in the occurrence and development of OA and as a new target for gene therapy.

Insights into The Function and Regulation of Jumonji C Lysine Demethylases as Hypoxic Responsive Enzymes

2020 ◽  
Vol 21 (7) ◽  
pp. 642-654
Author(s):  
Anand Chopra ◽  
Hemanta Adhikary ◽  
William G. Willmore ◽  
Kyle K. Biggar
Keyword(s):  
Catalytic Mechanism ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxic Response ◽  
Protein Targets ◽  
Nonhistone Protein ◽  
Oxygen Sensitive ◽  
Demethylase Activity ◽  
Hypoxic Tumor

Cellular responses to hypoxia (low oxygen) are governed by oxygen sensitive signaling pathways. Such pathways, in part, are controlled by enzymes with oxygen-dependent catalytic activity, of which the role of prolyl 4-hydroxylases has been widely reviewed. These enzymes inhibit hypoxic response by inducing the oxygen-dependent degradation of hypoxia-inducible factor 1α, the master regulator of the transcriptional hypoxic response. Jumonji C domain-containing lysine demethylases are similar enzymes which share the same oxygen-dependent catalytic mechanism as prolyl 4- hydroxylases. Traditionally, the role of lysine demethylases has been studied in relation to demethylation activity against histone substrates, however, within the past decade an increasing number of nonhistone protein targets have been revealed, some of which have a key role in survival in the hypoxic tumor microenvironment. Within this review, we highlight the involvement of methyllysine in the hypoxic response with a focus on the HIF signaling pathway, the regulation of demethylase activity by oxygen, and provide insights into notable areas of future hypoxic demethylase research.

scholarly journals tRNA-Dependent Import of a Transit Sequence-Less Aminoacyl-tRNA Synthetase (LeuRS2) into the Mitochondria of Arabidopsis

2021 ◽  
Vol 22 (8) ◽  
pp. 3808
Author(s):  
Steffen Reinbothe ◽  
Claudia Rossig ◽  
John Gray ◽  
Sachin Rustgi ◽  
Diter von Wettstein ◽  
...  
Keyword(s):  
Protein Complex ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Trna Synthetase ◽  
In Planta ◽  
Trna Synthetases ◽  
And Function

Aminoacyl-tRNA synthetases (AaRS) charge tRNAs with amino acids for protein translation. In plants, cytoplasmic, mitochondrial, and chloroplast AaRS exist that are all coded for by nuclear genes and must be imported from the cytosol. In addition, only a few of the mitochondrial tRNAs needed for translation are encoded in mitochondrial DNA. Despite considerable progress made over the last few years, still little is known how the bulk of cytosolic AaRS and respective tRNAs are transported into mitochondria. Here, we report the identification of a protein complex that ties AaRS and tRNA import into the mitochondria of Arabidopsis thaliana. Using leucyl-tRNA synthetase 2 (LeuRS2) as a model for a mitochondrial signal peptide (MSP)-less precursor, a ≈30 kDa protein was identified that interacts with LeuRS2 during import. The protein identified is identical with a previously characterized mitochondrial protein designated HP30-2 (encoded by At3g49560) that contains a sterile alpha motif (SAM) similar to that found in RNA binding proteins. HP30-2 is part of a larger protein complex that contains with TIM22, TIM8, TIM9 and TIM10 four previously identified components of the translocase for MSP-less precursors. Lack of HP30-2 perturbed mitochondrial biogenesis and function and caused seedling lethality during greening, suggesting an essential role of HP30-2 in planta.

scholarly journals Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuechai Chen ◽  
Jianan Wang ◽  
Muhammad Tahir ◽  
Fangfang Zhang ◽  
Yuanyuan Ran ◽  
...  
Keyword(s):  
Intervertebral Disc Degeneration ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Degradation Process ◽  
Human Diseases ◽  
Rna Modification ◽  
Rna Methylation ◽  
M6a Rna Methylation ◽  
The Impact

AbstractAutophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

scholarly journals Long noncoding RNAs as tumorigenic factors and therapeutic targets for renal cell carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Haiyan Shen ◽  
Guomin Luo ◽  
Qingjuan Chen
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Noncoding Rnas ◽  
Protein Translation ◽  
Long Noncoding Rnas ◽  
In Vivo Studies

AbstractApproximately 338,000 patients are diagnosed with kidney cancer worldwide each year, and renal cell carcinoma (RCC), which is derived from renal epithelium, accounts for more than ninety percent of the malignancy. Next generation RNA sequencing has enabled the identification of novel long noncoding RNAs (lncRNAs) in the past 10 years. Recent studies have provided extensive evidence that lncRNAs bind to chromatin modification proteins, transcription factors, RNA-binding proteins and microRNAs, and thereby modulate gene expression through regulating chromatin status, gene transcription, pre-mRNA splicing, mRNA decay and stability, protein translation and stability. In vitro and in vivo studies have demonstrated that over-expression of oncogenic lncRNAs and silencing of tumor suppressive lncRNAs are a common feature of human RCC, and that aberrant lncRNA expression is a marker for poor patient prognosis, and is essential for the initiation and progression of RCC. Because lncRNAs, compared with mRNAs, are expressed in a tissue-specific manner, aberrantly expressed lncRNAs can be better targeted for the treatment of RCC through screening small molecule compounds which block the interaction between lncRNAs and their binding proteins or microRNAs.

DT-03-02: Viewing neurodegeneration beyond the tangle: The role of RNA binding proteins in Alzheimer's disease

2013 ◽  
Vol 9 ◽  
pp. P847-P847
Author(s):  
Benjamin Wolozin ◽  
Tara Vanderweyde ◽  
Liqun Liu-Yesucevitz ◽  
Alpaslan Dedeoglu ◽  
Leonard Petrucelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins

scholarly journals Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4

2004 ◽  
Vol 379 (2) ◽  
pp. 283-289 ◽  
Author(s):  
Marie-Chloé BOULANGER ◽  
Tina Branscombe MIRANDA ◽  
Steven CLARKE ◽  
Marco di FRUSCIO ◽  
Beat SUTER ◽  
...  
Keyword(s):  
Rna Binding ◽  
Developmental Stages ◽  
Rna Binding Proteins ◽  
Genetic System ◽  
Arginine Methylation ◽  
Type I ◽  
Protein Arginine Methyltransferases ◽  
Arginine Residues ◽  
Drosophila Protein

The role of arginine methylation in Drosophila melanogaster is unknown. We identified a family of nine PRMTs (protein arginine methyltransferases) by sequence homology with mammalian arginine methyltransferases, which we have named DART1 to DART9 (Drosophilaarginine methyltransferases 1–9). In keeping with the mammalian PRMT nomenclature, DART1, DART4, DART5 and DART7 are the putative homologues of PRMT1, PRMT4, PRMT5 and PRMT7. Other DART family members have a closer resemblance to PRMT1, but do not have identifiable homologues. All nine genes are expressed in Drosophila at various developmental stages. DART1 and DART4 have arginine methyltransferase activity towards substrates, including histones and RNA-binding proteins. Amino acid analysis of the methylated arginine residues confirmed that both DART1 and DART4 catalyse the formation of asymmetrical dimethylated arginine residues and they are type I arginine methyltransferases. The presence of PRMTs in D. melanogaster suggest that flies are a suitable genetic system to study arginine methylation.

scholarly journals RNA Is a Double-Edged Sword in ALS Pathogenesis

2021 ◽  
Vol 15 ◽  
Author(s):  
Benjamin L. Zaepfel ◽  
Jeffrey D. Rothstein
Keyword(s):  
Motor Neurons ◽  
Cortical Neurons ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Metabolism ◽  
Small Subset ◽  
Toxic Rna ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

scholarly journals Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation

2018 ◽  
Author(s):  
Zhizhou Ye ◽  
Donald E. Ayer
Keyword(s):  
Protein Synthesis ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Aerobic Glycolysis ◽  
Protein Translation ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Coding Region ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

ABSTRACTOncogenic Ras upregulates aerobic glycolysis to meet the bioenergetic and biosynthetic demands of rapidly growing cells. In contrast, Thioredoxin interacting protein (TXNIP) is a potent inhibitor of glucose uptake and is frequently downregulated in human cancers. Our lab previously discovered that Ras activation suppresses TXNIP transcription and translation. In this report, we developed a system to study how Ras affects TXNIP translation in the absence of transcriptional affects. We show that whereas Ras drives a global increase in protein translation, it suppresses TXNIP protein synthesis by reducing the rate at which ribosomes transit the coding region of TXNIP mRNA. To investigate the underlying mechanism(s), we randomized or optimized the codons in the TXNIP message without altering the TXNIP primary amino acid sequence. Translation from these mRNA variants is still repressed by Ras, intimating that mRNA secondary structure, miRNAs, RNA binding proteins, or codon usage do not contribute to the blockade of TXNIP synthesis. Rather, we show that the N-terminus of the growing TXNIP polypeptide is the target for Ras-dependent translational repression. Our work demonstrates how Ras suppresses TXNIP translation elongation in the face of a global upregulation of protein synthesis and provides new insight into Ras-dependent metabolic reprogramming.

The Expanding Role of RNA-Binding Proteins in Neurodegeneration

2019 ◽  
pp. 373-403
Author(s):  
Bhawana Maurya ◽  
Satya Surabhi ◽  
Pranjali Pandey ◽  
Ashim Mukherjee ◽  
Mousumi Mutsuddi
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins
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