Journal Article

Proinflammatory cytokine TNF-α increases the stability of hepatitis B virus X protein through NF-κB signaling

Ruchi Shukla, Jiping Yue, Maha Siouda, Tarik Gheit, Olivier Hantz, Philippe Merle, Fabien Zoulim, Vladimir Krutovskikh, Massimo Tommasino and Bakary S. Sylla

in Carcinogenesis

Volume 32, issue 7, pages 978-985
Published in print July 2011 | ISSN: 0143-3334
Published online March 2011 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgr057
Proinflammatory cytokine TNF-α increases the stability of hepatitis B virus X protein through NF-κB signaling

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Hepatitis B virus (HBV) X protein (HBx) is a key player in HBV-induced hepatocellular carcinoma (HCC). HBx interacts with several cell signaling molecules, leading to activation of various transcription factors including nuclear factor-kappaB (NF-κB). Activated NF-κB signaling is implicated in many human cancers including HCC. Here, we present evidence that the NF-κB signaling activator, tumor necrosis factor (TNF)-α, induces the accumulation of HBx in cells by increasing protein stability due to reduced proteasomal degradation. The effects of TNF-α on HBx protein stability are mediated via activated NF-κB effector kinases IKKα and IKKβ and p65. The non-IKK-phosphorylable p65-S534A mutant did not induce HBx protein stability; hence, phosphorylation of p65 by IKK is a key step in TNF-α-induced stabilization of HBx. Phospho-p65 showed higher affinity to HBx compared with the non-phosphorylable p65 mutant, suggesting that the interaction of phospho-p65 with HBx might be important for HBx stabilization. We also show that the increased level of HBx in cells cooperates with TNF-α toward activation of NF-κB and expression of NF-κB-regulated genes, indicating a positive feedback loop between HBx and NF-κB signaling. Overall, our study provides evidence for interplay between HBx and NF-κB signaling, which may account for HBV-mediated liver carcinogenesis.

Journal Article.  6594 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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