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Gene expression and biological processes influenced by deletion of Stat3 in pulmonary type II epithelial cells.

ABSTRACT: The signal transducer and activator of transcription 3 (STAT3) mediates gene expression in response to numerous growth factors and cytokines, playing an important role in many cellular processes. To better understand the molecular mechanisms by which Stat3 influences gene expression in the lung, the effect of pulmonary epithelial cell specific deletion of Stat3 on genome wide mRNA expression profiling was assessed. Differentially expressed genes were identified from Affymetrix Murine GeneChips analysis and subjected to gene ontology classification, promoter analysis, pathway mapping and literature mining.Total of 791 mRNAs were significantly increased and 314 mRNAs were decreased in response to the deletion of Stat3Delta/Delta in the lung. STAT is the most enriched cis-elements in the promoter regions of those differentially expressed genes. Deletion of Stat3 induced genes influencing protein metabolism, transport, chemotaxis and apoptosis and decreased the expression of genes mediating lipid synthesis and metabolism. Expression of Srebf1 and 2, genes encoding key regulators of fatty acid and steroid biosynthesis, was decreased in type II cells from the Stat3Delta/Delta mice, consistent with the observation that lung surfactant phospholipids content was decreased. Stat3 influenced both pro- and anti-apoptotic pathways that determine cell death or survival. Akt, a potential transcriptional target of Stat3, was identified as an important participant in Stat3 mediated pathways including Jak-Stat signaling, apoptosis, Mapk signaling, cholesterol and fatty acid biosynthesis.Deletion of Stat3 from type II epithelial cells altered the expression of genes regulating diverse cellular processes, including cell growth, apoptosis and lipid metabolism. Pathway analysis indicates that STAT3 regulates cellular homeostasis through a complex regulatory network that likely enhances alveolar epithelial cell survival and surfactant/lipid synthesis, necessary for the protection of the lung during injury.

SUBMITTER: Xu Y

PROVIDER: S-EPMC2234434 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Gene expression and biological processes influenced by deletion of Stat3 in pulmonary type II epithelial cells.

Xu Yan Y Ikegami Machiko M Wang Yanhua Y Matsuzaki Yohei Y Whitsett Jeffrey A JA

BMC genomics 20071210

<h4>Background</h4>The signal transducer and activator of transcription 3 (STAT3) mediates gene expression in response to numerous growth factors and cytokines, playing an important role in many cellular processes. To better understand the molecular mechanisms by which Stat3 influences gene expression in the lung, the effect of pulmonary epithelial cell specific deletion of Stat3 on genome wide mRNA expression profiling was assessed. Differentially expressed genes were identified from Affymetrix ...[more]

PMID: 18070348

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Project description:Pulmonary alveoli contain two distinct populations of epithelial cells. Type II cells produce pulmonary surfactant lipids and surfactant-associated proteins (SP) required for maintaining alveolar surface tension at the air-liquid interface and host defense against respiratory pathogens. Type II cells are also progenitors for epithelial type I cells, a terminally differentiated elongated cell that covers microvascular endothelial cells and participates in gas exchange. Despite some indirect evidence, it is unknown whether subpopulations of type II cells exist. We created a line of transgenic mice expressing enhanced green fluorescent protein (EGFP) under control of the human SP-C promoter. Expression of EGFP may define a subpopulation of type II cells because it is 1) expressed in approximately 10% of type II cells, 2) appears much later in embryonic development than SP-C, and 3) selectively proliferates in mice infected with influenza A virus. To determine whether EGFP defines a unique subpopulation of type II cells, RNA was isolated from EGFP-positive and negative type II cells and hybridized to affymetrix arrays. Of the genes detected in EGFP-positive cells, most were equally detected in EGFP-negative cells. However, approximately 350 genes were selectively elevated ≥5-fold in EGFP-positive cells and 1500 genes selectively expressed by EGFP-negative cells. These findings suggest EGFP defines a subpopulation of type II epithelial cells in this line of transgenic mice. Type II cells were harvested from approximately 10 young adult (8-week) mice and sorted into EGFP-positive (sample EGFP-1) and EGFP-negative (sample nonEGFP-1) populations using a B-D FACSVantage SE cell sorter. RNA was prepared from approximately two million cells and hybridized to Affymetrix M430 2.0 array as a one by one comparison. The isolation and gene expression analysis of EGFP-positive and EGFP-negative type II cells was repeated a second (using EGFP-2 and nonEGFP-2 samples) and third (using EGFP-3 and nonEGFP-3 samples) time.

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Gene expression and biological processes influenced by deletion of Stat3 in pulmonary type II epithelial cells.

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Gene expression and biological processes influenced by deletion of Stat3 in pulmonary type II epithelial cells.

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