Xu Yan, Ikegami Machiko, Wang Yanhua, Matsuzaki Yohei, Whitsett Jeffrey A
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH, USA.
BMC Genomics. 2007 Dec 10;8:455. doi: 10.1186/1471-2164-8-455.
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.
信号转导及转录激活因子3（STAT3）介导基因表达以响应多种生长因子和细胞因子，在许多细胞过程中发挥重要作用。为了更好地理解Stat3影响肺中基因表达的分子机制，评估了肺上皮细胞特异性缺失Stat3对全基因组mRNA表达谱的影响。通过Affymetrix小鼠基因芯片分析鉴定差异表达基因，并进行基因本体分类、启动子分析、通路映射和文献挖掘。
肺中Stat3Delta/Delta缺失导致791个mRNA显著增加，314个mRNA减少。STAT是这些差异表达基因启动子区域中最丰富的顺式元件。Stat3缺失诱导影响蛋白质代谢、转运、趋化性和凋亡的基因表达，并降低介导脂质合成和代谢的基因表达。编码脂肪酸和类固醇生物合成关键调节因子的基因Srebf1和2在Stat3Delta/Delta小鼠的II型细胞中表达降低，这与肺表面活性物质磷脂含量降低的观察结果一致。Stat3影响决定细胞死亡或存活的促凋亡和抗凋亡途径。Akt是Stat3的潜在转录靶点，被确定为Stat3介导的途径（包括Jak-Stat信号传导、凋亡、Mapk信号传导、胆固醇和脂肪酸生物合成）中的重要参与者。
II型上皮细胞中Stat3的缺失改变了调节多种细胞过程（包括细胞生长、凋亡和脂质代谢）的基因表达。通路分析表明，STAT3通过一个复杂的调节网络调节细胞内稳态，该网络可能增强肺泡上皮细胞存活以及表面活性物质/脂质合成，这对于损伤期间肺的保护是必要的。
