The microtubule associated protein tau renders breast cancer cells tnf-alpha resistant by inhibiting tnf-receptor signaling
Item
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Title
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The microtubule associated protein tau renders breast cancer cells tnf-alpha resistant by inhibiting tnf-receptor signaling
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Identifier
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d_2009_2013:f0935ff4ddc0:12015
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identifier
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12702
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Creator
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Debnath, Shawon,
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Contributor
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Jimmie E. Fata
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Date
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2013
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biochemistry | Cellular biology | Molecular biology | Oncology | Breast cancer | Curcumin-Dendrimer | Cyclin D1 | Tau | TNF-alpha
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Abstract
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The pro-inflammatory cytokine Tumor Necrosis Factor alpha is often found in elevated concentration within the microenvironment of breast tumors. A number of findings have now established that TNFalpha can exert opposing effects on tumor cells - acting either as an anti-cancer agent or as a promoter of tumor progression. To date, mechanisms underlying these divergent outcomes have not been elucidated. Here, we demonstrate that tau, classically considered as a microtubule-associated protein, plays a key role to determine whether cancer cells respond negatively (apoptosis) or positively (proliferation) to TNFalpha exposure. Using RNAi knockdown experiments we show that up-regulation of tau protein in breast cancer cells is necessary for the acquisition of resistance to TNFalpha mediated cytotoxicity. In contrast, an analysis of generated stable cell lines overexpressing full-length tau indicates that tau can inhibit TNFalpha induced caspase activation and NFkappaB nuclear translocation. Site-directed mutagenesis has revealed that the N-terminal portion of tau, which does not bind to tubulin, is sufficient for this inhibition of TNFalpha signaling. Finally, mechanistic studies have uncovered that tau inhibits TNF-receptor trimerization and receptor clustering thereby blocking subsequent signaling. Taken together, we conclude that acquisition of TNFalpha resistance requires a previously undescribed mechanism involving up-regulation of tau, which in turn inhibits receptor trimerization and thus attenuates TNFalpha downstream signaling in tumor cells.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
