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Zhang, Y.* ; Handley, D.* ; Kaplan, T.* ; Yu, H. ; Bais, A.S.* ; Richards, T.* ; Pandit, K.V.* ; Zeng, Q.* ; Benos, P.V.* ; Friedman, N.* ; Eickelberg, O. ; Kaminski, N.*

High throughput determination of TGFβ1/SMAD3 targets in A549 lung epithelial cells.

PLoS ONE 6:e20319 (2011)
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BACKGROUND: Transforming growth factor beta 1 (TGFβ1) plays a major role in many lung diseases including lung cancer, pulmonary hypertension, and pulmonary fibrosis. TGFβ1 activates a signal transduction cascade that results in the transcriptional regulation of genes in the nucleus, primarily through the DNA-binding transcription factor SMAD3. The objective of this study is to identify genome-wide scale map of SMAD3 binding targets and the molecular pathways and networks affected by the TGFβ1/SMAD3 signaling in lung epithelial cells. METHODOLOGY: We combined chromatin immunoprecipitation with human promoter region microarrays (ChIP-on-chip) along with gene expression microarrays to study global transcriptional regulation of the TGFβ1/SMAD3 pathway in human A549 alveolar epithelial cells. The molecular pathways and networks associated with TGFβ1/SMAD3 signaling were identified using computational approaches. Validation of selected target gene expression and direct binding of SMAD3 to promoters were performed by quantitative real time RT-PCR and electrophoretic mobility shift assay on A549 and human primary lung epithelial cells. RESULTS AND CONCLUSIONS: Known TGFβ1 target genes such as SERPINE1, SMAD6, SMAD7, TGFB1 and LTBP3, were found in both ChIP-on-chip and gene expression analyses as well as some previously unrecognized targets such as FOXA2. SMAD3 binding of FOXA2 promoter and changed expression were confirmed. Computational approaches combining ChIP-on-chip and gene expression microarray revealed multiple target molecular pathways affected by the TGFβ1/SMAD3 signaling. Identification of global targets and molecular pathways and networks associated with TGFβ1/SMAD3 signaling allow for a better understanding of the mechanisms that determine epithelial cell phenotypes in fibrogenesis and carcinogenesis as does the discovery of the direct effect of TGFβ1 on FOXA2.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Idiopathic pulmonary-fibrosis; Growth-factor-beta; Surfactant protein-B; Endoplasmic-reticulum stress; Transcription Factor-I; Gene-expression data; TGF-Beta; Mesenchymal transition; Extracellular-matrix; Confers resistancce
Language english
Publication Year 2011
HGF-reported in Year 2011
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 6, Issue: 5, Pages: , Article Number: e20319 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Lung Research
PSP Element(s) G-501600-001
PubMed ID 21625455
DOI 10.1371/journal.pone.0020319
WOS ID WOS:000290793400056
Erfassungsdatum 2011-06-30
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