LEF1 isoforms regulate cellular senescence and aging.
LEF1 isoforms regulate cellular senescence and aging.
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作者：
对衰老及其机制（例如细胞衰老）的研究为与年龄相关的病理学提供了宝贵的见解，从而有助于其预防和治疗。当前丰富的高通量数据与强大的分析算法的激增相结合，促进了识别可能驱动这些病理的潜在途径的新方法。为了确定肺衰老的关键调节因子，我们对老年人与年轻人类受试者和小鼠的转录谱进行了比较分析，重点关注肺巨噬细胞、T 细胞和 B 免疫细胞转录调节中与年龄相关的常见变化。重要的是，我们在细胞培养测定和人肺样本中验证了我们的发现。我们的分析发现，淋巴增强子结合因子 1 (LEF1) 是不同组织和物种的所有三种细胞类型中基因表达的重要的年龄相关调节因子。后续实验表明，长、短LEF1亚型的差异表达是细胞衰老的关键调节机制。对特发性肺纤维化患者肺组织的进一步检查发现，LEF1 存在明显失调，特发性肺纤维化是一种与年龄相关的疾病，与细胞衰老密切相关。总的来说，我们的结果表明 LEF1 是衰老的关键因素，其差异调节与人类和小鼠细胞衰老有关。淋巴增强子结合因子 1 (LEF1) 调节子是人类和小鼠肺部以及人类血液中衰老的常见机制。实验证据支持长 LEF1 亚型通过可能的新调控机制部分逆转细胞衰老的直接功能作用。 IPF 中的 LEF1 表达和调节子活性表明在疾病的早期和晚期阶段存在多种作用模式。
The study of aging and its mechanisms, such as cellular senescence, has provided valuable insights into age‐related pathologies, thus contributing to their prevention and treatment. The current abundance of high‐throughput data combined with the surge of robust analysis algorithms has facilitated novel ways of identifying underlying pathways that may drive these pathologies. For the purpose of identifying key regulators of lung aging, we performed comparative analyses of transcriptional profiles of aged versus young human subjects and mice, focusing on the common age‐related changes in the transcriptional regulation in lung macrophages, T cells, and B immune cells. Importantly, we validated our findings in cell culture assays and human lung samples. Our analysis identified lymphoid enhancer binding factor 1 (LEF1) as an important age‐associated regulator of gene expression in all three cell types across different tissues and species. Follow‐up experiments showed that the differential expression of long and short LEF1 isoforms is a key regulatory mechanism of cellular senescence. Further examination of lung tissue from patients with idiopathic pulmonary fibrosis, an age‐related disease with strong ties to cellular senescence, revealed a stark dysregulation of LEF1. Collectively, our results suggest that LEF1 is a key factor of aging, and its differential regulation is associated with human and murine cellular senescence. Lymphoid enhancer‐binding factor 1 (LEF1) regulon is a common mechanism of aging in human and murine lungs and in human blood. Experimental evidence supports a direct functional role of the long LEF1 isoform in partially reversing cellular senescence through a possible new regulatory mechanism. LEF1 expression and regulon activity in IPF suggest a diverse mode of action during the early and late stages of the disease.
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影响因子：
7.8
作者：
通讯作者：
--
特发性肺纤维化的细胞衰老进展（综述）。
影响因子：
2.7
作者：
Han S;Lu Q;Liu X
通讯作者：
Liu X
影响因子：
5.9
作者：
Borcherding N;Vishwakarma A;Voigt AP;Bellizzi A;Kaplan J;Nepple K;Salem AK;Jenkins RW;Zakharia Y;Zhang W
通讯作者：
Zhang W
DOI：
10.1513/pats.200803-025hr
发表时间：
2008-09-15
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Franks, Teri J;Colby, Thomas V;Williams, Mary C
通讯作者：
Williams, Mary C
影响因子：
16.6
作者：
Angelidis, Ilias;Simon, Lukas M.;Schiller, Herbert B.
通讯作者：
Schiller, Herbert B.