Hepatitis B Virus X Protein Differentially Activates RAS-RAF-MAPK and JNK Pathways in X-transforming Versus Non-transforming AML12 Hepatocytes

Tarn, Chi; Lee, Sook; Hu, Yong; Ashendel, Curtis L.; Andrisani, Ourania M.

doi:10.1074/jbc.m104105200

Cited by 84 publications

(95 citation statements)

References 71 publications

(80 reference statements)

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“…In addition, pX sensitizes hepatocytes to apoptosis in response to weak apoptotic stimuli, such as subapoptotic concentrations of transforming growth factor ␤ (TGF-␤) or TNF-␣ (43,69) by an unknown mechanism. pX induces the activation of mitogenic Ras-Raf-MAP kinase (5,23,73), JNK (6,73), and p38 MAP kinase (72) pathways via calcium-regulated activation of c-Src (9,44). Importantly, earlier studies (72,73) employing pXexpressing hepatocyte cell lines demonstrated that tetracycline-regulated pX differentially activates the Ras-Raf-MAP kinase, JNK, and p38 MAP kinase pathways in differentiated versus less differentiated hepatocytes.…”

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confidence: 99%

“…pX induces the activation of mitogenic Ras-Raf-MAP kinase (5,23,73), JNK (6,73), and p38 MAP kinase (72) pathways via calcium-regulated activation of c-Src (9,44). Importantly, earlier studies (72,73) employing pXexpressing hepatocyte cell lines demonstrated that tetracycline-regulated pX differentially activates the Ras-Raf-MAP kinase, JNK, and p38 MAP kinase pathways in differentiated versus less differentiated hepatocytes. In differentiated hepatocytes, modeled by the AML12 3pX-1 cell line, conditional pX expression activates the Ras-Raf-MAP kinase pathway in a sustained manner (72).…”

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“…We employed a well-characterized cellular model (49,(71)(72)(73) in which sustained activation of the JNK and p38 MAP kinase pathways is mediated by tetracycline-regulated expression of the hepatitis B virus (HBV) X protein (pX). pX is required for the viral life cycle (90) and is implicated in the hepatocarcinogenesis of chronic HBV patients (11).…”

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Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-α Expression

Wang

Grégori

Hullinger

et al. 2004

Molecular and Cellular Biology

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Apoptosis is a physiologically regulated process of programmed cell death involved in embryonic development and in the maintenance of homeostasis (33, 58). The dysregulation of apoptosis results in disease, e.g., cancer and autoimmune and neurodegenerative disorders (27,75,88). Apoptosis is also the basis for therapies designed to target cancerous cells and limit cytotoxicity that results from drug treatment (42). Thus, the molecular mechanisms and signaling pathways regulating apoptosis are of great significance.The caspases mediating apoptosis include initiator caspases 8 and 9 and effector caspase 3 (25). Apoptosis occurs via two pathways: the extrinsic (death receptor) pathway, initiated by activation of members of the death receptor superfamily (Fas and tumor necrosis factor receptor 1 [TNFR1]), leading to caspase 8 activation (61), and the intrinsic (mitochondrial) pathway, resulting in the mitochondrial release of cytochrome c and caspase 9 activation (80). These two pathways converge upon the activation of caspase 3 (33). Mitochondrial involvement in apoptosis is determined by the balance of antiapoptotic (Bcl-2 and Bcl-X L ) and proapoptotic (Bax, Bad, Bid, and Noxa) Bcl-2 family members (46). Importantly, the extrinsic and intrinsic pathways are linked via the function of the protein Bid (80,81).Apoptosis is regulated by the p38 mitogen-activated protein (MAP) kinase/c-Jun N-terminal kinase (JNK) cellular stress pathways (47, 76). These pathways, members of the mitogenic family of signaling cascades (39), also mediate proliferation and differentiation (20,26,42,62,64,65). Evidence in support of JNK and p38 MAP kinase pathways in regulating apoptosis is derived from studies employing treatments simulating cellular stress. These stresses include growth factor withdrawal (21, 85), the presence of proinflammatory cytokines (8,56,67) and drugs (17,29,57,63), UV radiation (79), and overexpression of constitutively active effectors, e.g., MEKK1 (40), ASK-1 (31, 41), and JNK1 (51). However, despite reports of a role for the JNK and p38 MAP kinase in apoptosis and the demonstration that ASK-1 is upstream of both JNK and p38 MAP kinase pathways (37, 78), whether both pathways are necessary for apoptosis remains unresolved. For example, although both the p38 MAP kinase and JNK pathways are activated upon exposure to UV radiation (34), only the JNK pathway mediates UV-induced apoptosis in primary mouse fibroblasts (79). With other apoptotic treatments, e.g., by overexpression of constitutively active ASK-1 (31, 41), activation of the JNK pathway is the dominant event in mediating apoptosis, although ASK-1 is known to activate both the p38 MAP kinase and JNK pathways (37,78). Thus, despite the demonstrated role of the JNK pathway in apoptosis under robust apoptotic conditions, it is not yet

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Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-α Expression

Wang

Grégori

Hullinger

et al. 2004

Molecular and Cellular Biology

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“…These factors are involved in junB gene expression via MAP kinase pathways like p38, and ERK or via the JAK/STAT pathway (22,27,28,(36)(37)(38)(39)(40)(41)(42)(43)(44). A previous report verified that p38 was activated by various stress conditions, such as osmotic stimulus or cytokine, suggesting its relationship to cell death (45)(46)(47)(48)(49). ERK induced cell growth and differentiation and regulated cell cycle transition (50)(51)(52).…”

Section: Discussionmentioning

confidence: 95%

Expression of junB is markedly stimulated by glycyrrhizin in a human hepatoma cell line

Koike

2011

Oncol Rep

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“…9 Other studies have shown that the HBX protein of HBV augments Ras/Raf/MAPK signal transduction, which contributes to cell proliferation and survival. 34 From this evidence, we expected that Chang-HBX cells should harbor more active Ras protein when compared with Chang-vec cells. When we compared Ras expression in cell lysates from the two cell lines, we found that Ras protein is increased somewhat in abundance in Chang-HBX cells compared with that of Chang-vec cells (Figure 3a).…”

Section: Hbx Expression Causes Resistance To Reovirus-induced Apoptotmentioning

confidence: 99%

Expression of HBX, an oncoprotein of hepatitis B virus, blocks reoviral oncolysis of hepatocellular carcinoma cells

et al. 2008

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Although reovirus has been used in tests as a potential cancer therapeutic agent against a variety of cancer cells, its application to hepatocellular carcinoma cells, in which the hepatitis B virus (HBV) X (HBX) protein of HBV plays a primary role, has not yet been explored. Here, we describe experiments in which we use reovirus to treat Chang liver carcinoma cells expressing either a vector only (Chang-vec) or a vector encoding HBX protein (Chang-HBX). Although Chang-vec cells readily support reoviral proliferation and undergo apoptosis, Chang-HBX cells are highly resistant to reoviral infection and virus-induced apoptosis, even though HBX protein induces activation of Ras and inactivation of PKR, which are normally thought to enhance reoviral oncolysis. The resistance of Chang-HBX cells to reovirus may instead be explained by HBX-induced downregulation of death receptor 5 and activation of Stat1. Phosphorylated Stat1 activates interferon (IFN)-stimulated regulatory element (ISRE)-and IFN-g-activated sequence (GAS)-mediated transcription, leading to the production of IFN-b, whereas the reduced expression of Stat1 with its siRNA results in a decrease in IFN-b production, by which Chang-HBX cells eventually succumb to reovirus infection. This result further indicates that HBX induces the establishment of an antiviral state through Stat1 activation. Thus, it appears that active Ras does not override the antiviral effect mediated by the activation of Stat1. Accordingly, we report that HBX, an oncoprotein of HBV, can prevent reoviral oncolysis of hepatocellular carcinoma. This suggests there may be limits to the practical application of reovirus in the treatment of human cancers already expressing other oncoviral proteins.

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Hepatitis B Virus X Protein Differentially Activates RAS-RAF-MAPK and JNK Pathways in X-transforming Versus Non-transforming AML12 Hepatocytes

Cited by 84 publications

References 71 publications

Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-α Expression

Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-α Expression

Expression of junB is markedly stimulated by glycyrrhizin in a human hepatoma cell line

Expression of HBX, an oncoprotein of hepatitis B virus, blocks reoviral oncolysis of hepatocellular carcinoma cells

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