Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.
Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.
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Sox17 促进细胞周期进程并抑制 TGF-β/Smad3 信号传导以启动呼吸道上皮中的祖细胞行为。
DOI：
10.1371/journal.pone.0005711
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发表时间：
2009-05-27
期刊：
影响因子：
3.7
通讯作者：
Whitsett JA
中科院分区：
文献类型：
--
作者：
Lange AW;Keiser AR;Wells JM;Zorn AM;Whitsett JA
Sry相关的高迁移率族盒转录因子Sox 17是多种发育过程所必需的，包括内胚层形成、血管发育和胎儿造血干细胞维持。Sox 17在成熟呼吸道上皮细胞中的表达引起增殖和谱系重新指定，表明Sox 17可以改变成人肺祖细胞的命运。在本文中，我们确定的机制，Sox 17影响肺上皮祖细胞的行为和重新编程细胞的命运在成熟的呼吸道上皮。Sox 17在成年小鼠肺上皮细胞中的条件性表达表明，细胞簇的形成和肺泡祖细胞向近端气道谱系的重新指定是快速可逆的过程。Sox 17的长期表达导致肺泡区域中具有不同呼吸上皮细胞特征的细支气管样结构的异位形成。在祖细胞行为的起始过程中，Sox 17诱导增殖并增加祖细胞标志物Sca-1和参与细胞周期进程的基因的表达。值得注意的是，Sox 17在体内增强细胞周期蛋白D1的表达，并在体外激活细胞周期蛋白D1启动子活性。Sox 17可降低成年小鼠肺中转化生长因子-β（TGF-β）反应性细胞周期抑制因子（包括p15、p21和p57）的表达，并抑制TGF-β1介导的体外转录反应。Sox 17与Smad 3相互作用，阻断了Smad 3的DNA结合和转录活性。总之，这些数据表明，一个子集的成熟呼吸道上皮细胞保留显着的表型可塑性和Sox 17，早期内胚层形成所需的基因，激活细胞周期，并重新启动多能祖细胞的行为在成熟的肺细胞。
The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-β)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-β1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.
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DOI：
10.1016/b978-012370615-7/50077-9
发表时间：
2007-01-01
期刊：
PRINCIPLES OF TISSUE ENGINEERING, 3RD EDITION
影响因子：
--
作者：
Besnard, Valerie;Whitsett, Jeffrey A.
通讯作者：
Whitsett, Jeffrey A.
DOI：
10.1152/ajplung.00044.2002
发表时间：
2002-08-01
影响因子：
4.9
作者：
Liu, C;Morrisey, EE;Whitsett, JA
通讯作者：
Whitsett, JA
影响因子：
64.5
作者：
Hudson, C;Clements, D;Woodland, HR
通讯作者：
Woodland, HR
DOI：
10.1152/ajplung.1997.273.3.l572
发表时间：
1997-09-01
影响因子：
4.9
作者：
Buckley, S;Driscoll, B;Warburton, D
通讯作者：
Warburton, D
影响因子：
4.8
作者：
Bhaskaran, Manoj;Kolliputi, Narasaiah;Liu, Lin
通讯作者：
Liu, Lin