Stimulation of Inducible Nitric Oxide by Hepatitis B Virus Transactivator Protein HBx Requires MTA1 Coregulator

Bui-Nguyen, Tri M.; Pakala, Suresh B.; Sirigiri, Divijendranatha Reddy; Eisenacher, Martin; Murad, Ferid; Kumar, Rakesh

doi:10.1074/jbc.m109.065987

Cited by 43 publications

(32 citation statements)

References 49 publications

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“…HBx has been shown to induce the expression of metastasis-associated protein 1 (MTA1) coregulator, which is a master chromatin modifier involved in carcinogenesis and a positive regulator of inducible nitric oxide synthase (iNOS) transcription [57,80]. The HBx/MTA1 complex stimulates the production of NO, which has been implicated in hepatocarcinogenesis [57]. HBx has also been demonstrated to increase the expression of cyclooxygenase-2 (COX-2) mRNA and protein [81].…”

Section: Trans-activating Mechanisms Of Hbxmentioning

confidence: 98%

“…Secondly, the upregulation of inflammatory mediators by HBx is another pathway of interest. HBx has been shown to induce the expression of metastasis-associated protein 1 (MTA1) coregulator, which is a master chromatin modifier involved in carcinogenesis and a positive regulator of inducible nitric oxide synthase (iNOS) transcription [57,80]. The HBx/MTA1 complex stimulates the production of NO, which has been implicated in hepatocarcinogenesis [57].…”

Section: Trans-activating Mechanisms Of Hbxmentioning

confidence: 99%

“…1 Structure of hepatitis B virus (HBV) genome. The genome of HBV is a double-stranded DNA (3.2 kb), which contains four overlapping open reading frames (ORFs) coding for viral envelope (pre-S1/pre-S2/S), core proteins (pre-C/C), viral polymerase, and HBx protein (X) induction of nitric oxide synthetase [56,57] and Fas ligand [58,59]. Resistance to Fas-mediated apoptosis in HepG2 cells was demonstrated to be responsible for the transactivation of the NFjB family by HBx via SAPK/Janus Kinase (JAK) pathway activation [19,26], whereas the tumor necrosis factor (TNF)-a signaling pathway was shown to be regulated by HBx via NFAT activation in the cyclosporine A-dependent pathway [60].…”

Section: Trans-activating Mechanisms Of Hbxmentioning

confidence: 99%

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Hepatitis B virus X gene and hepatocarcinogenesis

2011

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Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor in hepatocellular carcinoma (HCC), which is one of the most common cancers worldwide. The pathogenesis of HBV-mediated hepatocarcinogenesis is, however, incompletely understood. Evidence suggests that the HBV X protein (HBx) plays a crucial role in HCC development. HBx is a multifunctional regulator that modulates transcription, signal transduction, cell cycle progression, apoptosis, protein degradation pathways, and genetic stability through interaction with host factors. This review describes the current state of knowledge of the molecular pathogenesis of HBV-induced HCC, with a focus on the role of HBx in hepatocarcinogenesis.

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Section: Trans-activating Mechanisms Of Hbxmentioning

confidence: 98%

Section: Trans-activating Mechanisms Of Hbxmentioning

confidence: 99%

Section: Trans-activating Mechanisms Of Hbxmentioning

confidence: 99%

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Hepatitis B virus X gene and hepatocarcinogenesis

2011

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“…It is a component of the nuclear remodeling and histone deacetylase complex involved in carcinogenesis. MTA1 is a positive regulator of inducible nitric oxide synthase (iNOS) transcription as well (Bui-Nguyen et al, 2010). The HBx/MTA1 complex stimulates the production of nitric oxide (NO°), by stimulation of iNOS expression in an NF-κB-dependent manner.…”

Section: Effects Of Hbx Protein On Signal Transduction and Transcriptmentioning

confidence: 99%

Hepatitis B virus-induced hepatocellular carcinoma: The role of the virus x protein

Motavaf¹,

Safari²,

Jourshari³

et al. 2013

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Summary. -Hepatocellular carcinoma (HCC) is one of the most common malignant diseases and has the fourth highest mortality rate worldwide. Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor in HCC. Currently available evidence support a critical role of hepatitis B virus x (HBx) gene and protein in the pathogenesis of HBV-induced HCC. HBx protein is a multifunctional regulator that modulates cellular signal transduction pathways, transcriptional regulations, cell cycle progress, DNA repair, apoptosis, and genetic stability by interacting with different host factors. This review describes the current state of knowledge about the biological roles of this protein in the development of HCC. Abbreviations: DNMTs = DNA methyltransferases; HBV = hepatitis B virus; HBx = hepatitis B x protein; HCC = hepatocellular carcinoma; MMP = matrix metalloproteinase; MTA = metastasisassociated protein; RAR-β2 = retinoic acid receptor β2; TSGs = tumor suppressor genes; XPB = xeroderma pigmentosum B

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“…Several reports represented a positive correlation between the expression of NF-B and TG2 expression (32,33) and between the expression of NF-B and MTA1 (8,16,34), suggesting the existence of a positive regulatory mechanism among these genes. Increased TG2 activity triggers NF-B activation by inducing the polymerization of I-B␣ rather than stimulating I-B␣ kinase (35).…”

Section: Resultsmentioning

confidence: 99%

MTA1 Coregulation of Transglutaminase 2 Expression and Function during Inflammatory Response

Ghanta¹,

Pakala²,

Reddy

et al. 2011

Journal of Biological Chemistry

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Although both metastatic tumor antigen 1 (MTA1), a master chromatin modifier, and transglutaminase 2 (TG2), a multifunctional enzyme, are known to be activated during inflammation, it remains unknown whether these molecules regulate inflammatory response in a coordinated manner. Here we investigated the role of MTA1 in the regulation of TG2 expression in bacterial lipopolysaccharide (LPS)-stimulated mammalian cells. While studying the impact of MTA1 status on global gene expression, we unexpectedly discovered that MTA1 depletion impairs the basal as well as the LPS-induced expression of TG2 in multiple experimental systems. We found that TG2 is a chromatin target of MTA1 and of NF-B signaling in LPSstimulated cells. In addition, LPS-mediated stimulation of TG2 expression is accompanied by the enhanced recruitment of MTA1, p65RelA, and RNA polymerase II to the NF-B consensus sites in the TG2 promoter. Interestingly, both the recruitment of p65 and TG2 expression are effectively blocked by a pharmacological inhibitor of the NF-B pathway. These findings reveal an obligatory coregulatory role of MTA1 in the regulation of TG2 expression and of the MTA1-TG2 pathway, at least in part, in LPS modulation of the NF-B signaling in stimulated macrophages.Inflammation is an adaptive immune response triggered by the body against detrimental stimuli and conditions such as microbial infection and tissue injury (1, 2). Inflammation is usually a healing response, but it becomes detrimental if targeted destruction and assisted repair are not properly activated (3). Primarily, macrophages and mast cells recognize the infection and produce a wide variety of inflammatory mediators such as chemokines, cytokines, etc., all contributing to the elicitation of an inflammatory response (1). The inflammatory response is characterized by coordinated regulation of signaling pathways that regulate the expression of both the pro-inflammatory and the anti-inflammatory cytokines including IL-1, IL-6, TNF-␣, receptor activator of NF-B ligand (RANKL), etc. (4). The inability of host to regulate inflammatory response results in sepsis, organ dysfunction, and even death (5). These inflammatory cytokines are under the tight control of master gene transcriptional factor NF-B in promoting the inflammation, and in turn, innate immunity (6). Furthermore, transcriptional control of such NF-B genomic targets is also under a tight control of nucleosome-remodeling coregulators and complexes, leading to either the stimulation or the repression of gene transcription at the molecular level (7-10).In recent times, metastatic tumor antigen 1 (MTA1) 3 has been recognized as one of the major coregulators in mammalian cells. MTA1 is a ubiquitously expressed chromatin modifier, having an integral role in nucleosome-remodeling and histone deacetylase (NuRD) complexes (11). MTA1 is widely up-regulated in a wide variety of human tumors and has been shown to play a role in tumorigenesis (11-14). MTA1 regulates transcription of its targets by modifying the acetylation stat...

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Stimulation of Inducible Nitric Oxide by Hepatitis B Virus Transactivator Protein HBx Requires MTA1 Coregulator

Cited by 43 publications

References 49 publications

Hepatitis B virus X gene and hepatocarcinogenesis

Hepatitis B virus X gene and hepatocarcinogenesis

Hepatitis B virus-induced hepatocellular carcinoma: The role of the virus x protein

MTA1 Coregulation of Transglutaminase 2 Expression and Function during Inflammatory Response

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