Abstract
Transforming growth factor β (TGF-β) functions as a tumor suppressor in premalignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF-β are proposed to be dictated by different partners of its downstream effector Smads. However, the mechanism for the contextual changes of Smad partners remained undefined. Here, we demonstrate that 14-3-3ζ destabilizes p53, a Smad partner in premalignant mammary epithelial cells, by downregulating 14-3-3σ, thus turning off TGF-β's tumor suppression function. Conversely, 14-3-3ζ stabilizes Gli2 in breast cancer cells, and Gli2 partners with Smads to activate PTHrP and promote TGF-β-induced bone metastasis. The 14-3-3ζ-driven contextual changes of Smad partners from p53 to Gli2 may serve as biomarkers and therapeutic targets of TGF-β-mediated cancer progression.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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14-3-3 Proteins / genetics*
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Bone Neoplasms / genetics*
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Bone Neoplasms / pathology
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Bone Neoplasms / secondary
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Epithelial-Mesenchymal Transition / genetics
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Female
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Humans
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Kruppel-Like Transcription Factors / genetics*
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Molecular Targeted Therapy
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Neoplasm Metastasis
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Nuclear Proteins / genetics*
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Promoter Regions, Genetic
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Smad Proteins / genetics
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Transforming Growth Factor beta / genetics*
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Tumor Suppressor Protein p53 / genetics*
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Zinc Finger Protein Gli2
Substances
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14-3-3 Proteins
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GLI2 protein, human
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Kruppel-Like Transcription Factors
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Nuclear Proteins
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Smad Proteins
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TP53 protein, human
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Transforming Growth Factor beta
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Tumor Suppressor Protein p53
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YWHAZ protein, human
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Zinc Finger Protein Gli2
Associated data
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GEO/GSE52032
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GEO/GSE52066