Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein-protein interactions can be regulated by protein modifications such as phosphorylation. Some of the phosphorylation sites (Ser155, Ser162 and Ser170) of HBV (hepatitis B virus) Cp have been discovered and these sites are implicated in the regulation of viral genome encapsidation, capsid localization and nucleocapsid maturation. In the present report, the dimeric form of HBV Cp was phosphorylated by PKA (protein kinase A), but not by protein kinase C in vitro, and the phosphorylation of dimeric Cp facilitated HBV core assembly. Matrix-assisted laser-desorption ionization-time-of-flight analysis revealed that the HBV Cp was phosphorylated at Ser87 by PKA. This was further confirmed using a mutant HBV Cp with S87G mutation. The S87G mutation inhibited the phosphorylation and, as a result, the in vitro HBV core assembly was not facilitated by PKA. In addition, when either pCMV/FLAG-Core(WT) or pCMV/FLAG-Core(S87G) was transfected into HepG2 cells, few mutant Cps (S87G) assembled into capsids compared with the wild-type (WT) Cps, although the same level of total Cps was expressed in both cases. In conclusion, PKA facilitates HBV core assembly through phosphorylation of the HBV Cp at Ser87.
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PMID:Phosphorylation of hepatitis B virus Cp at Ser87 facilitates core assembly. 1674 Jan 37

The HBx (X protein of hepatitis B virus) is a promiscuous transactivator implicated to play a key role in hepatocellular carcinoma. However, HBx-regulated molecular events leading to deregulation of cell cycle or establishment of a permissive environment for hepatocarcinogenesis are not fully understood. Our cell culture-based studies suggested that HBx had a profound effect on cell cycle progression even in the absence of serum. HBx presence led to an early and sustained level of cyclin-cdk2 complex during the cell cycle combined with increased protein kinase activity of cdk2 heralding an early proliferative signal. The increased cdk2 activity also led to an early proteasomal degradation of p27(Kip1) that could be reversed by HBx-specific RNA interference and blocked by a chemical inhibitor of cdk2 or the T187A mutant of p27. Further, our co-immunoprecipitation and in vitro binding studies with recombinant proteins suggested a direct interaction between HBx and the cyclin E/A-cdk2 complex. Interference with different signalling cascades known to be activated by HBx suggested a constitutive requirement of Src kinases for the association of HBx with these complexes. Notably, the HBx mutant that did not interact with cyclin E/A failed to destabilize p27(Kip1) or deregulate the cell cycle. Thus HBx appears to deregulate the cell cycle by interacting with the key cell cycle regulators independent of its well-established role in transactivation.
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PMID:HBx-dependent cell cycle deregulation involves interaction with cyclin E/A-cdk2 complex and destabilization of p27Kip1. 1693 21

The hepatitis B virus infects more than 350 million people worldwide and is a leading cause of liver cancer. The virus encodes a multifunctional regulator, the hepatitis B virus X protein (HBx), that is essential for virus replication. HBx is involved in modulating signal transduction pathways and transcription mediated by various factors, notably CREB that requires the recruitment of the co-activators CREB-binding protein (CBP)/p300. Here we investigated the role of HBx and its potential interaction with CBP/p300 in regulating CREB transcriptional activity. We show that HBx and CBP/p300 synergistically enhanced CREB activity and that CREB phosphorylation by protein kinase A was a prerequisite for the cooperative action of HBx and CBP/p300. We further show that HBx interacted directly with CBP/p300 in vitro and in vivo. Using chromatin immunoprecipitation, we provide evidence that HBx physically occupied the CREB-binding domain of CREB-responsive promoters of endogenous cellular genes such as interleukin 8 and proliferating cell nuclear antigen. Moreover expression of HBx increased the recruitment of p300 to the interleukin 8 and proliferating cell nuclear antigen promoters in cells, and this is associated with increased gene expression. As recruitment of CBP/p300 is known to represent the limiting event for activating CREB target genes, HBx may disrupt this cellular regulation, thus predisposing cells to transformation.
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PMID:The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription. 3211 23

We previously demonstrated that activation of NF-kappaB by the hepatitis B virus X (HBx) gene plays an important role in cell survival. In the present study, we explored the upstream mediators of NF-kappaB activation and their correlations with cell survival. XTT assays and colony generation assays revealed that inhibition of NF-kappaB activation indeed increased cell death in HBx-expressing cells. Utilizing inactivating mutants of signal transducers, we showed that dominant negative mutants of stress-activated protein kinase/extracellular signal-regulated kinase (SEK1) or PKCalpha significantly diminished the HBx-mediated NF-kappaB activation. However, neither of these mutants significantly affected the cell survival in colony generation assays. In contrast, inactivating mutants of Raf-1 or PKB (protein kinase B)/Akt abrogated the HBx-mediated NF-kappaB activation and also suppressed the cell survival. Our results suggest that the Raf-1 or PKB-mediated NF-kappaB activation promotes cell survival in HBx-expressing cells.
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PMID:Raf-1 and protein kinase B regulate cell survival through the activation of NF-kappaB in hepatitis B virus X-expressing cells. 1718 75

The human hepatitis B virus (HBV) X protein (HBx) plays a crucial role(s) in the viral life cycle and contributes to the onset of hepatocellular carcinoma (HCC). HBx caused the mitochondrial translocation of Raf-1 kinase either alone or in the context of whole-viral-genome transfections. Mitochondrial translocation of Raf-1 is mediated by HBx-induced oxidative stress and was dependent upon the phosphorylation of Raf-1 at the serine338/339 and Y340/341 residues by p21-activated protein kinase 1 and Src kinase, respectively. These studies provide an insight into the mechanisms by which HBV induces intracellular events relevant to liver disease pathogenesis, including HCC.
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PMID:Hepatitis B virus X protein stimulates the mitochondrial translocation of Raf-1 via oxidative stress. 1742 66

DNA methyltransferase 1 (DNMT1) is responsible for copying DNA methylation patterns to the daughter strands during DNA replication. Its expression is frequently up-regulated in human tumors, including hepatocellular carcinoma, but the mechanism of overexpression and its biological significance remain unclear. Here, we show that hepatitis B virus X protein (HBx) activates DNMT1 expression via a regulatory circuit involving the p16(INK4a)-cyclin D1-cyclin-dependent kinase (CDK) 4/6-retinoblastoma protein (pRb)-E2F1 pathway. HBx induced DNA hypermethylation of p16(INK4a) promoter to repress its expression, which subsequently led to activation of G1-CDKs, phosphorylation of pRb, activation of E2F1, and finally transcriptional activation of DNMT1. Inhibition of DNMT1 activity by either treatment with 5'-Aza-2'dC or introduction of DNMT1 small interfering RNA not only abolished the DNA methylation-mediated p16(INK4a) repression but also impaired DNMT1 expression itself, suggesting a cross-talk between DNMT1 and p16(INK4a). The up-regulation of cyclin D1 by HBx is likely to serve as an initiative impulse for the circuit because it was absolutely required for the activation of DNMT1 expression. We also observed that accumulated DNMT1 via this pathway inactivates E-cadherin expression through promoter hypermethylation. Considering that the pRb-E2F1 pathway is commonly activated in human tumors, activation of this circuit might be widespread and a potential therapeutic target.
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PMID:Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 pathway. 1757 44

(-)-Epigallocatechin-3-gallate (EGCG), a major component of green tea, protects against certain types of cancers, although the mechanism has not yet been determined. It was previously demonstrated that EGCG blocks aryl hydrocarbon receptor (AhR)-mediated transcription induced by the potent carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Unlike other AhR antagonists that directly bind to the AhR, EGCG inhibits AhR-mediated transcription by binding to hsp90. We hypothesize that EGCG exerts anti-AhR and anticancer effects by acting as an hsp90 inhibitor. Using proteolytic footprinting, immunoprecipitation, and an ATP-agarose pull-down assay, EGCG was found to directly modulate the conformation of hsp90 and bind at or near to a C-terminal ATP binding site. Hsp90 chaperone function, as assessed by its ability to mediate refolding of denatured luciferase, was inhibited by EGCG treatment. Hsp90 dimerization, which occurs at the C-terminal end, was also inhibited by EGCG treatment. Coimmunoprecipitation studies showed that EGCG stabilizes an AhR complex that includes hsp90 and XAP2 (hepatitis B virus X-associated protein 2), and decreases the association of aryl hydrocarbon nuclear translocator (Arnt) with ligand-activated AhR. Thus, EGCG, through its ability to bind to hsp90, blocks AhR response element (AhRE) recognition. These studies indicate a novel mechanism whereby EGCG inhibits ligand-induced AhRE binding and AhR-mediated transcriptional activity. In EGCG-treated human ovarian carcinoma SKOV3 cells, decreased levels of several cancer-related hsp90 client proteins, such as ErbB2, Raf-1 and phospho-AKT, were observed. EGCG also modified the association of hsp90 with several cochaperones. Overall, these data indicate that EGCG is a novel hsp90 inhibitor. Further studies are needed to determine if this has a role in the antitumor actions of EGCG.
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PMID:(-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor. 1911 37

Hepatocellular carcinoma (HCC) accounts for 6% of all cancers worldwide. In the United States, the incidence is expected to increase due to the increased rate of hepatitis C viral infection affecting that region. Other factors that will influence higher incidence rates for HCC include the persistent presence of alcoholic cirrhosis and the recently recognized correlation between non-alcoholic steatohepatitis (NASH) and HCC. In most cases, cirrhosis is an integral part of the morbidity and mortality associated with HCC, and must be accounted for in order to manage patients with HCC properly. Historically, medical oncologists used the Child-Pugh scoring system of cirrhosis. However, Child-Pugh only categorizes the cirrhosis and does not address factors intrinsic to the cancer itself, which is recognized as a major limitation of that system. The idea of incorporating cancer-related parameters was developed by several research groups. The Cancer of the Liver Italian Program (CLIP) score and the Chinese University Prognostic Index (CUPI) are among many others that were developed and are of great use for patients with hepatitis C- and hepatitis B-associated HCC, respectively. Many chemotherapeutic agents have been tested in HCC, with reported response rates between 10% and 15% and no demonstrated survival advantage. Over the past decade, several molecular targets involved in the etiology of HCC have been identified. Recently, sorafenib, an antiangiogenic and Raf kinase inhibitor, has shown a survival advantage. The innovative therapeutic outcomes associated with novel targeted therapies illustrates the need for biologic and pharmacokinetic end points to define their optimal doses and therapeutic effects.
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PMID:Current management of advanced hepatocellular carcinoma. 1925 98

Little is known about the parameters and factors that determine the intracellular distribution of the hepatitis B virus core protein (HBc). In order to study HBc in living cells, HBc was tagged with green fluorescent protein (GFP). Being assembly-incompetent, the GFP-fusion protein was distributed equally throughout the cell. Mutational inactivation of known serine-phosphorylation sites within the C-terminal region led to predominantly intranuclear localization. Phosphorylation of these targets, presumably by an SR domain protein kinase, resulted in a predominantly cytoplasmic localization, which suggests active cytoplasmic export or retention. The phosphoserine itself, and not its negative charge, appears essential for the underlying mechanism. In addition, the arginine-rich, protamine-like domain surrounding these phosphorylation sites does not function as the dominant nuclear-localization signal, as had been assumed previously, because neither deleting nor altering these sequences led to a change in intracellular HBc subunit distribution. Restoring the capability of the fusion protein to form capsids by co-assembly with assembly-competent, sterically uncompromised HBc subunits provided a second assay that gave insight into the effects resulting from capsid formation. Assembly was found to be the dominant factor in the cytoplasmic retention of the GFP-HBc fusion protein. Furthermore, the stability of these empty capsids was influenced by the cell-cycle inhibitor nocodazole. Thus, the intracellular distribution of HBc is dominated by cytoplasmic assembly, which is supported by the active nuclear export of HBc subunits, and modulated during the cell cycle by the instability of capsids.
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PMID:Assembly and export determine the intracellular distribution of hepatitis B virus core protein subunits. 1974 Oct 67

Capsids of hepatitis B virus and other hepadnaviruses contain a cellular protein kinase, which phosphorylates the capsid protein. Some phosphorylation sites are shown to be essential for distinct steps of viral replication as pregenome packaging or plus strand DNA synthesis. Although different protein kinases have been reported to phosphorylate the capsid protein, varying experimental approaches do not allow direct comparison. Furthermore, the activity of a specific protein kinase has not yet been correlated to steps in the hepadnaviral life cycle. In this study we show that capsids from various sources encapsidate active protein kinase Calpha, irrespective of hepatitis B virus genotype and host cell. Treatment of a virion expressing cell line with a pseudosubstrate inhibitor showed that inhibition of protein kinase C phosphorylation did not affect genome maturation but resulted in capsid accumulation and inhibited virion release to the medium. Our results imply that different protein kinases have distinct functions within the hepadnaviral life cycle.
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PMID:Inhibition of protein kinase C phosphorylation of hepatitis B virus capsids inhibits virion formation and causes intracellular capsid accumulation. 2010 60


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