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Prion protein is required for tumor necrosis factor ? (TNF?)-triggered nuclear factor ?B (NF-?B) signaling and cytokine production.

ABSTRACT: The expression of normal cellular prion protein (PrP) is required for the pathogenesis of prion diseases. However, the physiological functions of PrP remain ambiguous. Here, we identified PrP as being critical for tumor necrosis factor (TNF) ?-triggered signaling in a human melanoma cell line, M2, and a pancreatic ductal cell adenocarcinoma cell line, BxPC-3. In M2 cells, TNF? up-regulates the expression of p-I?B-kinase ?/? (p-IKK?/?), p-p65, and p-JNK, but down-regulates the I?B? protein, all of which are downstream signaling intermediates in the TNF receptor signaling cascade. When PRNP is deleted in M2 cells, the effects of TNF? are no longer detectable. More importantly, p-p65 and p-JNK responses are restored when PRNP is reintroduced into the PRNP null cells. TNF? also activates NF-?B and increases TNF? production in wild-type M2 cells, but not in PrP-null M2 cells. Similar results are obtained in the BxPC-3 cells. Moreover, TNF? activation of NF-?B requires ubiquitination of receptor-interacting serine/threonine kinase 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). TNF? treatment increases the binding between PrP and the deubiquitinase tumor suppressor cylindromatosis (CYLD), in these treated cells, binding of CYLD to RIP1 and TRAF2 is reduced. We conclude that PrP traps CYLD, preventing it from binding and deubiquitinating RIP1 and TRAF2. Our findings reveal that PrP enhances the responses to TNF?, promoting proinflammatory cytokine production, which may contribute to inflammation and tumorigenesis.

SUBMITTER: Wu GR

PROVIDER: S-EPMC5704461 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Prion protein is required for tumor necrosis factor α (TNFα)-triggered nuclear factor κB (NF-κB) signaling and cytokine production.

Wu Gui-Ru GR Mu Tian-Chen TC Gao Zhen-Xing ZX Wang Jun J Sy Man-Sun MS Li Chao-Yang CY

The Journal of biological chemistry 20170912 46

The expression of normal cellular prion protein (PrP) is required for the pathogenesis of prion diseases. However, the physiological functions of PrP remain ambiguous. Here, we identified PrP as being critical for tumor necrosis factor (TNF) α-triggered signaling in a human melanoma cell line, M2, and a pancreatic ductal cell adenocarcinoma cell line, BxPC-3. In M2 cells, TNFα up-regulates the expression of p-IκB-kinase α/β (p-IKKα/β), p-p65, and p-JNK, but down-regulates the IκBα protein, all o ...[more]

PMID: 28900035

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Dataset Information

Prion protein is required for tumor necrosis factor ? (TNF?)-triggered nuclear factor ?B (NF-?B) signaling and cytokine production.

Publications

Prion protein is required for tumor necrosis factor α (TNFα)-triggered nuclear factor κB (NF-κB) signaling and cytokine production.

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