Journal article
A microRNA network regulates expression and biosynthesis of wild-type and ΔF508 mutant cystic fibrosis transmembrane conductance regulator
Proceedings of the National Academy of Sciences - PNAS, Vol.109(33), pp.13362-13367
08/14/2012
DOI: 10.1073/pnas.1210906109
PMCID: PMC3421220
PMID: 22853952
Abstract
Production of functional proteins requires multiple steps, including gene transcription and posttranslational processing. MicroRNAs (miRNAs) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that miRNA-138 regulates
CFTR
expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with an miR-138 mimic increased
CFTR
mRNA and also enhanced CFTR abundance and transepithelial Cl
−
permeability independent of elevated mRNA levels. An miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common
CFTR
mutation, ΔF508, causes protein misfolding, protein degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-ΔF508 and restored Cl
−
transport to cystic fibrosis airway epithelia. This miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process more broadly than recognized previously. This discovery also provides therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation.
Details
- Title: Subtitle
- A microRNA network regulates expression and biosynthesis of wild-type and ΔF508 mutant cystic fibrosis transmembrane conductance regulator
- Creators
- Shyam Ramachandran - Department of PediatricsPhilip H Karp - Department of Internal Medicine, andPeng Jiang - Department of Internal Medicine, andLynda S Ostedgaard - Department of Internal Medicine, andAmy E Walz - Department of PediatricsJohn T Fisher - Department of Anatomy and Cell Biology, Carver College of MedicineShaf Keshavjee - Division of Thoracic Surgery, Toronto General Hospital, University Health NetworkKim A Lennox - , CoralvilleAshley M Jacobi - , CoralvilleScott D Rose - , CoralvilleMark A Behlke - , CoralvilleMichael J Welsh - Interdisciplinary Program in GeneticsYi Xing - Interdisciplinary Program in GeneticsPaul B McCray - Department of Pediatrics
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.109(33), pp.13362-13367
- DOI
- 10.1073/pnas.1210906109
- PMID
- 22853952
- PMCID
- PMC3421220
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Alternative title
- MicroRNA network regulation of CFTR biosynthesis
- Language
- English
- Date published
- 08/14/2012
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Neurosurgery; Internal Medicine
- Record Identifier
- 9984013204602771
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