Abstract
Detachment of epithelial cells from matrix or attachment to an inappropriate matrix engages an apoptotic response known as anoikis, which prevents metastasis. Cellular sensitivity to anoikis is compromised during the oncogenic epithelial-to-mesenchymal transition (EMT), through unknown mechanisms. We report here a pathway through which EMT confers anoikis resistance. NRAGE (neurotrophin receptor-interacting melanoma antigen) interacted with a component of the E-cadherin complex, ankyrin-G, maintaining NRAGE in the cytoplasm. Oncogenic EMT downregulated ankyrin-G, enhancing the nuclear localization of NRAGE. The oncogenic transcriptional repressor protein TBX2 interacted with NRAGE, repressing the tumor suppressor gene p14ARF. P14ARF sensitized cells to anoikis; conversely, the TBX2/NRAGE complex protected cells against anoikis by downregulating this gene. This represents a novel pathway for the regulation of anoikis by EMT and E-cadherin.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Ankyrins / genetics
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Ankyrins / metabolism
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Anoikis / physiology*
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Cadherins / genetics
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Cadherins / metabolism*
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Cell Line, Tumor
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Epithelial Cells / cytology
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Epithelial Cells / physiology
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Epithelial-Mesenchymal Transition / physiology*
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Humans
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction / physiology*
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism
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Tumor Suppressor Protein p14ARF / genetics
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Tumor Suppressor Protein p14ARF / metabolism
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Two-Hybrid System Techniques
Substances
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ANK3 protein, human
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Ankyrins
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Antigens, Neoplasm
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Cadherins
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MAGED1 protein, human
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Maged1 protein, mouse
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Neoplasm Proteins
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RNA, Small Interfering
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T-Box Domain Protein 2
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T-Box Domain Proteins
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Tumor Suppressor Protein p14ARF