期刊
MOLECULAR BIOLOGY OF THE CELL
卷 23, 期 5, 页码 781-791出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E11-06-0537
关键词
-
类别
资金
- National Institutes of Health [EB00262, HL73305, GM74048]
- Center for Engineering Cells and Regeneration of the University of Pennsylvania
- National Science Foundation
- National Research Service [F32 AR054219-01]
The transforming growth factor-beta (TGF-beta) signaling pathway is often misregulated during cancer progression. In early stages of tumorigenesis, TGF-beta acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis. However, as the disease progresses, TGF-beta switches to promote tumorigenic cell functions, such as epithelial-mesenchymal transition (EMT) and increased cell motility. Dramatic changes in the cellular microenvironment are also correlated with tumor progression, including an increase in tissue stiffness. However, it is unknown whether these changes in tissue stiffness can regulate the effects of TGF-beta. To this end, we examined normal murine mammary gland cells and Madin-Darby canine kidney epithelial cells cultured on polyacrylamide gels with varying rigidity and treated with TGF-beta 1. Varying matrix rigidity switched the functional response to TGF-beta 1. Decreasing rigidity increased TGF-beta 1-induced apoptosis, whereas increasing rigidity resulted in EMT. Matrix rigidity did not change Smad signaling, but instead regulated the PI3K/Akt signaling pathway. Direct genetic and pharmacologic manipulations further demonstrated a role for PI3K/Akt signaling in the apoptotic and EMT responses. These findings demonstrate that matrix rigidity regulates a previously undescribed switch in TGF-beta-induced cell functions and provide insight into how changes in tissue mechanics during disease might contribute to the cellular response to TGF-beta.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据