| Matrix rigidity regulates a switch between TGF-β1-induced apoptosis and epithelial-mesenchymal transition. | |
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MedLine Citation:
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PMID: 22238361 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The transforming growth factor-β (TGF-β) signaling pathway is often misregulated during cancer progression. In early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis. However, as the disease progresses, TGF-β 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 if these changes in tissue stiffness can regulate the effects of TGF-β. To this end, we examined NMuMG and MDCK epithelial cells cultured on polyacrylamide gels with varying rigidity and treated with TGF-β1. Interestingly, changing matrix rigidity switched the functional response to TGF-β1. Decreasing rigidity increased TGF-β1-induced apoptosis, while 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-β-induced cell functions and provide insight into how changes in tissue mechanics during disease may contribute to the cellular response to TGF-β. |
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Authors:
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Jennifer L Leight; Michele A Wozniak; Sophia Chen; Michelle L Lynch; Christopher S Chen |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-11 |
Journal Detail:
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Title: Molecular biology of the cell Volume: - ISSN: 1939-4586 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9201390 Medline TA: Mol Biol Cell Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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