Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors

The major surfactant protein, SP-A (a product of the SFTPA gene), serves as a marker of type II pneumocyte differentiation and surfactant synthesis. SFTPA expression in cultured human fetal lung (HFL) epithelial cells is upregulated by hormones that increase cyclic AMP (cAMP) and activate TTF-1/NKX2...

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Publicado no:Mol Cell Biol
Main Authors: Mishra, Ritu, Benlhabib, Houda, Guo, Wei, Lerma Cervantes, Connie B., Mendelson, Carole R.
Formato: Artigo
Idioma:Inglês
Publicado em: American Society for Microbiology 2018
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Research Article
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC5954188/
https://ncbi.nlm.nih.gov/pubmed/29507184
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1128/MCB.00037-18
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spelling pubmed-59541882018-11-15 Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors Mishra, Ritu Benlhabib, Houda Guo, Wei Lerma Cervantes, Connie B. Mendelson, Carole R. Mol Cell Biol Research Article The major surfactant protein, SP-A (a product of the SFTPA gene), serves as a marker of type II pneumocyte differentiation and surfactant synthesis. SFTPA expression in cultured human fetal lung (HFL) epithelial cells is upregulated by hormones that increase cyclic AMP (cAMP) and activate TTF-1/NKX2.1 and NF-κB. To further define mechanisms for type II cell differentiation and induction of SP-A, we investigated roles of microRNAs (miRNAs). Using microarray to identify differentially expressed miRNAs in HFL epithelial cells during type II cell differentiation in culture, we observed that members of the miRNA 199a (miR-199a)/miR-214 cluster were significantly downregulated during differentiation. Validated and predicted targets of miR-199a-3p/miR-199a-5p and miR-214, which serve roles in type II cell differentiation (COX-2, NF-κB p50/p65, and CREB1), and the CREB1 target, C/EBPβ, were coordinately upregulated. Accordingly, overexpression of miR-199a-5p, miR-199a-3p, or miR-214 mimics in cultured HFL epithelial cells decreased COX-2, NF-κB p50/p65, CREB1, and C/EBPβ proteins, with an associated inhibition of SP-A expression. Interestingly, overexpression of the EMT factor, ZEB1, which declines during cAMP-induced type II cell differentiation, increased pri-miR-199a and reduced the expression of the targets NF-κB/p50 and COX-2. Collectively, these findings suggest that the developmental decline in miR-199a/miR-214 in HFL causes increased expression of critical targets that enhance type II cell differentiation and SP-A expression. American Society for Microbiology 2018-05-15 /pmc/articles/PMC5954188/ /pubmed/29507184 http://dx.doi.org/10.1128/MCB.00037-18 Text en Copyright © 2018 American Society for Microbiology. https://doi.org/10.1128/ASMCopyrightv2 All Rights Reserved (https://doi.org/10.1128/ASMCopyrightv2) .
institution US NLM
collection PubMed Central
language Inglês
format Artigo
topic Research Article
spellingShingle Research Article
Mishra, Ritu
Benlhabib, Houda
Guo, Wei
Lerma Cervantes, Connie B.
Mendelson, Carole R.
Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors
description The major surfactant protein, SP-A (a product of the SFTPA gene), serves as a marker of type II pneumocyte differentiation and surfactant synthesis. SFTPA expression in cultured human fetal lung (HFL) epithelial cells is upregulated by hormones that increase cyclic AMP (cAMP) and activate TTF-1/NKX2.1 and NF-κB. To further define mechanisms for type II cell differentiation and induction of SP-A, we investigated roles of microRNAs (miRNAs). Using microarray to identify differentially expressed miRNAs in HFL epithelial cells during type II cell differentiation in culture, we observed that members of the miRNA 199a (miR-199a)/miR-214 cluster were significantly downregulated during differentiation. Validated and predicted targets of miR-199a-3p/miR-199a-5p and miR-214, which serve roles in type II cell differentiation (COX-2, NF-κB p50/p65, and CREB1), and the CREB1 target, C/EBPβ, were coordinately upregulated. Accordingly, overexpression of miR-199a-5p, miR-199a-3p, or miR-214 mimics in cultured HFL epithelial cells decreased COX-2, NF-κB p50/p65, CREB1, and C/EBPβ proteins, with an associated inhibition of SP-A expression. Interestingly, overexpression of the EMT factor, ZEB1, which declines during cAMP-induced type II cell differentiation, increased pri-miR-199a and reduced the expression of the targets NF-κB/p50 and COX-2. Collectively, these findings suggest that the developmental decline in miR-199a/miR-214 in HFL causes increased expression of critical targets that enhance type II cell differentiation and SP-A expression.
author Mishra, Ritu
Benlhabib, Houda
Guo, Wei
Lerma Cervantes, Connie B.
Mendelson, Carole R.
author_facet Mishra, Ritu
Benlhabib, Houda
Guo, Wei
Lerma Cervantes, Connie B.
Mendelson, Carole R.
author_sort Mishra, Ritu
title Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors
title_short Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors
title_full Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors
title_fullStr Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors
title_full_unstemmed Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors
title_sort developmental decline in the microrna 199a (mir-199a)/mir-214 cluster in human fetal lung promotes type ii cell differentiation by upregulating key transcription factors
publisher American Society for Microbiology
container_title Mol Cell Biol
publishDate 2018
url https://ncbi.nlm.nih.gov/pmc/articles/PMC5954188/
https://ncbi.nlm.nih.gov/pubmed/29507184
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1128/MCB.00037-18
_version_ 1821314637734346752

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