IGFBP7's susceptibility to proteolysis is altered by A‐to‐I RNA editing of its transcript

Sie, Christina Godfried; Hesler, Stephen; Maas, Stefan; Kuchka, Michael R.

doi:10.1016/j.febslet.2012.06.037

Cited by 26 publications

(23 citation statements)

References 32 publications

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“…Adenosine–to-inosine (A-to-I) editing is the most widespread form of RNA editing in higher eukaryotes and occurs most frequently within noncoding sequences; however, it also occurs in coding sequences [82, 83]. The extent of editing at these sites may change during development, or show cell or tissue-specificity [84, 85].…”

Section: Codon-optimization Altered Mrna Editing New Protein Ensemblesmentioning

confidence: 99%

“…Although A-to-I editing did not affect Nova 1 functional activity, protein half-life was increased. Similarly, tissue-specific A-to-I editing appears to affect the proteolytic processing of the human insulin-like growth factor-binding protein 7 (IGFBP7) which yields variants with different biological activities that may alter cell-extracellular matrix interactions [83]. …”

Section: Codon-optimization Altered Mrna Editing New Protein Ensemblesmentioning

confidence: 99%

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A critical analysis of codon optimization in human therapeutics

Mauro

Chappell

2014

Trends in Molecular Medicine

257

191

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Codon-optimization describes gene engineering approaches that use synonymous codon changes to increase protein production. Applications for codon-optimization include recombinant protein drugs and nucleic acid therapies, including gene therapy, mRNA therapy, and DNA/RNA vaccines. However, recent reports indicate that codon-optimization can affect protein conformation and function, increase immunogenicity, and reduce efficacy. We critically review this subject, identifying additional potential hazards including some unique to nucleic acid therapies. This analysis highlights the evolved complexity of codon usage and challenges the scientific bases for codon-optimization. Consequently, codon-optimization may not provide the optimal strategy for increasing protein production and may decrease the safety and efficacy of biotech therapeutics. We suggest that the use of this approach is reconsidered, particularly for in vivo applications.

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Section: Codon-optimization Altered Mrna Editing New Protein Ensemblesmentioning

confidence: 99%

Section: Codon-optimization Altered Mrna Editing New Protein Ensemblesmentioning

confidence: 99%

A critical analysis of codon optimization in human therapeutics

Mauro

Chappell

2014

Trends in Molecular Medicine

257

191

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“…In addition to creating synonymous and non-synonymous codon changes, several additional functional and regulatory implications were also found for editing. RNA editing is involved in several processes, including: alteration of pre-mRNA splicing by the creation or elimination of splice sites [10-12]; RNA degradation [13,14]; viral RNA replication [15]; nuclear retention of transcripts [16]; miRNA regulation [17,18]; and protein susceptibility to proteolytic cleavage [19]. …”

Section: Introductionmentioning

confidence: 99%

Mammalian conserved ADAR targets comprise only a small fragment of the human editosome

2014

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BackgroundADAR proteins are among the most extensively studied RNA binding proteins. They bind to their target and deaminate specific adenosines to inosines. ADAR activity is essential, and the editing of a subset of their targets is critical for viability. Recently, a huge number of novel ADAR targets were detected by analyzing next generation sequencing data. Most of these novel editing sites are located in lineage-specific genomic repeats, probably a result of overactivity of editing enzymes, thus masking the functional sites. In this study we aim to identify the set of mammalian conserved ADAR targets.ResultsWe used RNA sequencing data from human, mouse, rat, cow, opossum, and platypus to define the conserved mammalian set of ADAR targets. We found that the conserved mammalian editing sites are surprisingly small in number and have unique characteristics that distinguish them from non-conserved ones. The sites that constitute the set have a distinct genomic distribution, tend to be located in genes encoding neurotransmitter receptors or other synapse related proteins, and have higher editing and expression levels. We also found a high consistency of editing levels of this set within mice strains and between human and mouse. Tight regulation of editing in these sites across strains and species implies their functional importance.ConclusionsDespite the discovery of numerous editing targets, only a small number of them are conserved within mammalian evolution. These sites are extremely highly conserved and exhibit unique features, such as tight regulation, and probably play a pivotal role in mammalian biology.

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“…Among these, IGFBP5 is the most conserved member of high-affinity IGF binding protein. IGFBP7 supports cell adhesion and stimulates the proliferation of fibroblasts 33 , which is similar to tumor-derived adhesion factor (TAF) identified in human bladder carcinoma cell lines as a cell adhesion molecule 34 . However, in response to external cues, cells regulate the function of IGFBP7 by proteolytic cleavage 33 , which abolishes its function as a growth enhancer 35 .…”

Section: Discussionmentioning

confidence: 72%

Material-induced Senescence (MIS): Fluidity Induces Senescent Type Cell Death of Lung Cancer Cells via Insulin-Like Growth Factor Binding Protein 5

2017

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Objective: We propose here material-induced senescence (MIS) as a new therapeutic concept that limits cancer progression by stable cell cycle arrest. This study examined for the first time the effect of material fluidity on cellular senescence in lung carcinoma using poly(ε-caprolactone-co-D, L-lactide) (P(CL-co-DLLA)) with tunable elasticity and fluidity.Methods: The fluidity was varied by chemically crosslinking the polymer networks: the crosslinked P(CL-co-DLLA) shows solid-like properties with a stiffness of 260 kPa, while the non-crosslinked polymer exists in a quasi-liquid state with loss and storage moduli of 33 kPa and 11 kPa, respectively.Results: We found that cancer cells growing on the non-crosslinked, fluidic substrate undergo a non-apoptotic form of cell death and the cell cycle was accumulated in a G0/G1 phase. Next, we investigated the expression of biomarkers that are associated with cancer pathways. The cancer cells on the fluidic substrate expressed several biomarkers associated with senescence such as insulin-like growth factor binding protein 5 (IGFBP5). This result indicates that when cancer cells sense fluidity in their surroundings, the cells express IGFBP5, which in turn triggers the expression of tumor suppressor protein 53 and initiates cell cycle arrest at the G1 phase followed by cellular senescence. Furthermore, the cancer cells on the fluidic substrate maintained their epithelial phenotype, suggesting that the cancer cells do not undergo epithelial to mesenchymal transition.Conclusion: By considering these results as the fundamental information for MIS, our system could be applied to induce senescence in treatment-resistant cancers such as metastatic cancer or cancer stem cells.

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IGFBP7's susceptibility to proteolysis is altered by A‐to‐I RNA editing of its transcript

Cited by 26 publications

References 32 publications

A critical analysis of codon optimization in human therapeutics

A critical analysis of codon optimization in human therapeutics

Mammalian conserved ADAR targets comprise only a small fragment of the human editosome

Material-induced Senescence (MIS): Fluidity Induces Senescent Type Cell Death of Lung Cancer Cells via Insulin-Like Growth Factor Binding Protein 5

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