ArticleThe Journal of biological chemistry2014
Progranulin transcripts with short and long 5' untranslated regions (UTRs) are differentially expressed via posttranscriptional and translational repression.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 37 citations in OpenAlex.
- Article
- Targeting Granulin Haploinsufficiency in Frontotemporal Dementia: From Genetic Mechanisms to Therapeutics.International journal of molecular sciences · 2025Review
- The regulatory landscape of 5' UTRs in translational control during zebrafish embryogenesis.Developmental cell · 2025Article
- The Recent Research Progress of the Tumor mRNA Vaccine.Vaccines · 2024Review
- Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes.Genome biology · 2024Article
- Codon-optimization in gene therapy: promises, prospects and challenges.Frontiers in bioengineering and biotechnology · 2024Review
- Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease.Journal of neuroinflammation · 2023Review
- The regulatory landscape of 5' UTRs in translational control during zebrafish embryogenesis.bioRxiv : the preprint server for biology · 2023Article
- The Functional Meaning of 5'UTR in Protein-Coding Genes.International journal of molecular sciences · 2023Review
- The role of upstream open reading frames in translation regulation in the apicomplexan parasitesParasitology · 2021Review
- Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities.Frontiers in molecular neuroscience · 2021Review
- Approaches to develop therapeutics to treat frontotemporal dementia.Neuropharmacology · 2020Review
- Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Progranulin: Functions and neurologic correlations.Neurology · 2018Article
- The Receptor-interacting Serine/Threonine Protein Kinase 1 (RIPK1) Regulates Progranulin Levels.The Journal of biological chemistry · 2017Article
- The state of play in higher eukaryote gene annotation.Nature reviews. Genetics · 2016Review
- Decoding sORF translation - from small proteins to gene regulation.RNA biology · 2016Review
- Reduced miR-659-3p Levels Correlate with Progranulin Increase in Hypoxic Conditions: Implications for Frontotemporal Dementia.Frontiers in molecular neuroscience · 2016Article
- Upstream open reading frame in 5'-untranslated region reduces titin mRNA translational efficiency.Biochemical and biophysical research communications · 2014Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Frontotemporal lobar degeneration is associated with cytoplasmic or nuclear deposition of the TAR DNA-binding protein 43 (TDP-43). Haploinsufficiency of progranulin (GRN) is a major genetic risk factor for frontotemporal lobar degeneration associated with TDP-43 deposition. Therefore, understanding the mechanisms that control cellular expression of GRN is required not only to understand disease etiology but also for the development of potential therapeutic strategies. We identified different GRN transcripts with short (38-93 nucleotides) or long (219 nucleotides) 5' UTRs and demonstrate a cellular mechanism that represses translation of GRN mRNAs with long 5' UTRs. The long 5' UTR of GRN mRNA contains an upstream open reading frame (uORF) that is absent in all shorter transcripts. Because such UTRs can be involved in translational control as well as in mRNA stability, we compared the expression of GRN in cells expressing cDNAs with and without 5' UTRs. This revealed a selective repression of GRN translation and a reduction of mRNA levels by the 219-nucleotide-long 5' UTR. The specific ability of this GRN 5' UTR to repress protein expression was further confirmed by its transfer to an independent reporter. Deletion analysis identified a short stretch between nucleotides 76 and 125 containing two start codons within one uORF that is required and sufficient for repression of protein expression. Mutagenesis of the two AUG codons within the uORF is sufficient to reduce translational repression. Therefore initiating ribosomes at the AUGs of the uORF fail to efficiently initiate translation at the start codon of GRN. In parallel the 5' UTR also affects mRNA stability; thus two independent mechanisms determine GRN expression via mRNA stability and translational efficiency.
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