河马信号通路
细胞生物学
成纤维细胞
细胞外基质
癌症研究
纤维化
基因敲除
肺纤维化
辅活化剂
生物
CTGF公司
化学
信号转导
生长因子
转录因子
细胞培养
病理
受体
医学
遗传学
基因
作者
Fei Liu,David Lagares,Kyoung Moo Choi,Lauren Stopfer,Аleksandar Marinković,Vladimir Vrbanac,Clemens K. Probst,Samantha E. Hiemer,Thomas H. Sisson,Jeffrey C. Horowitz,Iván O. Rosas,Laura E. Fredenburgh,Carol Feghali‐Bostwick,Xaralabos Varelas,Andrew M. Tager,Daniel J. Tschumperlin
出处
期刊:American Journal of Physiology-lung Cellular and Molecular Physiology
[American Physiological Society]
日期:2015-02-15
卷期号:308 (4): L344-L357
被引量:562
标识
DOI:10.1152/ajplung.00300.2014
摘要
Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.
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