Cancer syndromes and therapy by stop-codon readthrough

Bordeira–Carriço, Renata; Pêgo, Ana Paula; Santos, Manuel A. S.; Oliveira, Carla

doi:10.1016/j.molmed.2012.09.004

Cited by 63 publications

(51 citation statements)

References 85 publications

(178 reference statements)

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“…Ribosomal subunits do not efficiently dissociate from the translated mRNA when stalling at a premature stop codon if it is not closely followed by a poly(A) signal. Indeed, proper translation termination depends on a stimulating signal from the poly(A) binding protein and therefore only occurs when the stop codon is in spatial proximity of the poly(A) tail region (26)(27)(28). For that reason, we speculate that the transcription machinery can read through the two stop codons (TAA followed by TGA) in the case of the manipulated ERβ gene.…”

Section: Discussionmentioning

confidence: 98%

Estrogen receptor β exon 3-deleted mouse: The importance of non-ERE pathways in ERβ signaling

Maneix

Antonson

Humire

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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In 1998, an estrogen receptor β (ERβ) knockout (KO) mouse was created by interrupting the gene at the DNA binding domain (DBD) with a neocassette. The mutant females were subfertile and there were abnormalities in the brain, prostate, lung, colon, and immune system. In 2008, another ERβ mutant mouse was generated by deleting ERβ exon 3 which encodes the first zinc finger in the DBD. The female mice of this strain were unable to ovulate but were otherwise normal. The differences in the phenotypes of the two KO strains, have led to questions about the physiological function of ERβ. In the present study, we created an ERβ exon 3-deleted mouse (ERβ-Δex3) and confirmed that the only observable defect was anovulation. Despite the two in-frame stop codons introduced by splicing between exons 2 and 4, an ERβ protein was expressed in nuclei of prostate epithelial cells. Using two different anti-ERβ antibodies, we showed that an in-frame ligand binding domain and C terminus were present in the ERβ-Δex3 protein. Moreover, with nuclear extracts from ERβ-Δex3 prostates, there was an ERβ-dependent retardation of migration of activator protein-1 response elements in EMSA. Unlike the original knockout mouse, expression of Ki67, androgen receptor, and Dachshund-1 in prostate epithelium was not altered in the ERβ-Δex3 mouse. We conclude that very little of ERβ transcriptional activity depends on binding to classical estrogen response elements (EREs).mouse model | nuclear receptors | targeted disruption | ventral prostate | AP-1

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Section: Discussionmentioning

confidence: 98%

Estrogen receptor β exon 3-deleted mouse: The importance of non-ERE pathways in ERβ signaling

Maneix

Antonson

Humire

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In practical terms, this represents the introduction of a missense mutation that may be deleterious in most cancer-associated syndromes. 10 The use of sup-tRNAs allows circumventing this problem as tRNA-mediated nonsense suppression can lead to incorporation of the cognate, and therefore WT, amino acid at the PTC site. 10 To analyse the frequency of nonsense mutations in HDGC spectrum, we performed an extensive analysis of CDH1 mutations described to date in HDGC, LBC and EODGC, and identified 25 families with nonsense mutations.…”

Section: Resultsmentioning

confidence: 99%

“…10 The use of sup-tRNAs allows circumventing this problem as tRNA-mediated nonsense suppression can lead to incorporation of the cognate, and therefore WT, amino acid at the PTC site. 10 To analyse the frequency of nonsense mutations in HDGC spectrum, we performed an extensive analysis of CDH1 mutations described to date in HDGC, LBC and EODGC, and identified 25 families with nonsense mutations. Only eight different sup-tRNAs would be required to induce nonsense suppression in these patients and their families.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, sup-tRNAs could constitute a therapeutic tool for diseases caused by nonsense mutations, beyond Duchenne muscular dystrophy and cystic fibrosis, such as b-thalassaemia, 44 neurodegenerative diseases 45 or haemophilia, where the efficiency of aminoglycosides or PTC124 is yet to be demonstrated. 10 The use of sup-tRNA-based therapy in clinical practice faces many challenges, especially regarding the efficiency of delivery and expression of these systems in vivo, with a minimal toxicity caused to the organism. Plasmid-based systems and viral vectors raise several issues, such as toxicity, the risk of insertional mutagenesis, gene silencing or the induction of immune response within the organism.…”

Section: Resultsmentioning

confidence: 99%

“…6 Approximately 80% of germline CDH1 mutations are truncating, 7-9 20% of which are nonsense. 10 Missense mutations, present in B20% of HDGC families, may be highly deleterious. 2 …”

Section: Introductionmentioning

confidence: 99%

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Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

et al. 2014

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Hereditary diffuse gastric cancer (HDGC) syndrome, although rare, is highly penetrant at an early age, and is severe and incurable because of ineffective screening tools and therapy. Approximately 45% of HDGC families carry germline CDH1/Ecadherin alterations, 20% of which are nonsense leading to premature protein truncation. Prophylactic gastrectomy is the only recommended approach for all asymptomatic CDH1 mutation carriers. Suppressor-tRNAs can replace premature stop codons (PTCs) with a cognate amino acid, inducing readthrough and generating full-length proteins. The use of suppressor-tRNAs in HDGC patients could therefore constitute a less invasive therapeutic option for nonsense mutation carriers, delaying the development of gastric cancer. Our analysis revealed that 23/108 (21.3%) of E-cadherin-mutant families carried nonsense mutations that could be potentially corrected by eight suppressor-tRNAs, and arginine was the most frequently affected amino acid. Using site-directed mutagenesis, we developed an arginine suppressor-tRNA vector to correct one HDGC nonsense mutation. E-cadherin-deficient cell lines were transfected with plasmids carrying simultaneously the suppressor-tRNA and wild-type or mutant CDH1 mini-genes. RT-PCR, western blot, immunofluorescence, flow cytometry and proximity ligation assay (PLA) were used to establish the model, and monitor mRNA and protein expression and function recovery from CDH1 vectors. Cells expressing a CDH1 mini-gene, carrying a nonsense mutation and the suppressor-tRNA, recovered full-length E-cadherin expression and its correct localization and incorporation into the adhesion complex. This is the first demonstration of functional recovery of a mutated causative gene in hereditary cancer by cognate amino acid replacement with suppressor-tRNAs. Of the HDGC families, 21.3% are candidates for correction with suppressor-tRNAs to potentially delay cancer onset.

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Nonsense‐mediated decay factor SMG7 sensitizes cells to TNFα‐induced apoptosis via CYLD tumor suppressor and the noncoding oncogene Pvt1

et al. 2020

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Yang et al . found that mutation of the nonsense‐mediated decay factor SMG7 enhanced resistance to tumor necrosis factor (TNF)‐induced apoptosis via two oncogenic pathways. Downregulation of CYLD and overexpression of the long noncoding RNA Pvt1 converge to promote NF‐κB activation. The results indicate a composite tumor suppressor role for SMG7 in response to TNF.

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Cancer syndromes and therapy by stop-codon readthrough

Cited by 63 publications

References 85 publications

Estrogen receptor β exon 3-deleted mouse: The importance of non-ERE pathways in ERβ signaling

Estrogen receptor β exon 3-deleted mouse: The importance of non-ERE pathways in ERβ signaling

Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

Nonsense‐mediated decay factor SMG7 sensitizes cells to TNFα‐induced apoptosis via CYLD tumor suppressor and the noncoding oncogene Pvt1

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