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

---

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

Interferons exhibit antiviral and immunomodulatory properties. Antiviral effects appear mainly mediated via 2'5' oligoadenylate synthetase and protein kinase proteins which inhibit viral components synthesis. Interferons also influence the immune system through various mechanism among whom an increased expression of HLA class I antigens on hepatocyte plasma membrane and the promotion of natural killer cell activity leading to the clearance of infected hepatocytes. We report the results of various alpha interferon therapeutic regimens in 60 patients with chronic hepatitis C. In our series, 20 patients (33%) achieved a complete response but 78% of them relapsed after therapy withdrawal. Predictors of good response include young age, low serum ALT levels and mild liver injury. On the contrary, cirrhosis is associated with a poorer response.
...
PMID:[Chronic viral hepatitis and interferons: preliminary results in 60 patients with chronic hepatitis C and cellular mechanism of action]. 781 Feb 72

Chronic hepatitis resulting from hepatitis C virus (HCV) infection develops into cirrhosis in at least half of infected patients and increases the risk of hepatocellular carcinoma. The pathogenic effects of a number of viruses result from the disturbance of intracellular signal cascades caused by viral antigens. Therefore, we investigated the interaction of nonstructural protein 3 (NS3) of HCV with the cyclic AMP-dependent signal pathway. We found a similarity between the HCV sequence Arg-Arg-Gly-Arg-Thr-Gly-Arg-Gly-Arg-Arg-Gly-Ile-Tyr-Arg localized in NS3 and the general consensus sequence of protein kinase A (PKA). Consequently, the catalytic (C) subunit of PKA bound to a bacterially expressed fragment of HCV polyprotein containing amino acid residues 1189 to 1525. When this fragment was introduced into cells, it inhibited the translocation of the C subunit into the nucleus after stimulation with forskolin. The result of this inhibition was significantly reduced histone phosphorylation. Therefore, the presence of NS3 in the cytoplasm of infected cells may affect a wide range of PKA functions and contribute to the pathogenesis of the diseases caused by HCV.
...
PMID:Nonstructural protein 3 of hepatitis C virus blocks the distribution of the free catalytic subunit of cyclic AMP-dependent protein kinase. 906 Jun 39

Amplification found in a number of cyclin genes, especially in cyclin D and E, is an important event process that takes place in cancers, including hepatocellular carcinoma (HCC). The activities of a wide range of cell cycle-related kinases remain obscure in HCC. The purpose of the present study is to determine the cyclins and kinase activities of HCC in Long-Evans Cinnamon (LEC) rats. Cyclin D1, E, A, H, Cdk1(cyclin-dependent kinase; Cdc2), Cdk4, and Cdk6 protein levels were determined by Western blot analysis at different pathologic stages of liver tissues exhibiting HCC. Enzymatic activities of cyclin D1, E, A, Cdk4, Cdk6, Cdc2, Cdk7, and Wee1 kinase were measured by in-gel kinase assay. Protein levels and kinase activities of cyclin D1, E, Cdk4, cyclin A, and Wee1 increased proportionally with the development of HCC, especially in the transition process from chronic hepatitis to HCC. Although Cdc2 kinase activity was found to increase slightly from normal liver to chronic hepatitis, its activity remained unchanged in the process from chronic hepatitis to HCC. Cdk6 and Cdk7 activities remained unchanged in the process from normal liver to HCC. These data suggest that the increase in Cdc2 kinase may play a role in the process from normal liver to chronic hepatitis, whereas the predominant increase in cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 suggests involvement not only in the process from normal liver to chronic hepatitis, but also during transition into HCC.
...
PMID:Hepatocellular carcinoma cell cycle: study of Long-Evans cinnamon rats. 1100 14

As a part of the defense mechanism of the host to viral infection, interferons induce the transcription of several genes. These interferon-inducible genes contribute to the eradication of the viruses. Whereas some studies suggested the participation of a dsRNA-dependent protein kinase in the host reaction to hepatitis C virus infection, the involvement of other interferon-inducible genes has not been evaluated. Furthermore, there has been no analysis on the expression profile of multiple interferon-inducible genes. The aim of this study was to clarify the hepatic mRNA expression profile of interferon-inducible genes with a special concern to chronic hepatitis C. A total of 76 liver biopsy samples (28 with chronic hepatitis C, 10 with chronic hepatitis B, 9 with alcoholic liver disease, 14 with autoimmune hepatitis, 10 with primary biliary cirrhosis, and 5 of normal liver) were enrolled. The expression of the following genes was quantified by competitive reverse transcription-polymerase chain reaction and was compared according to the etiology; dsRNA-dependent protein kinase (PKR), 2',5'-oligoadenylate synthetase (2,5-AS), latent cellular endoribonuclease (RNase L), RNase L inhibitor, and MxA. As a result, PKR mRNA was significantly overexpressed in the liver of chronic hepatitis C compared with those of other etiologies (P =.0178), and it correlated significantly with serum alanine transaminase values (r =.51, P =.0054). Also, the expression of the RNase L inhibitor showed a significant reduction in chronic hepatitis C (P =.0184). The expressions of 2,5-AS, RNase L, and MxA were not different significantly irrespective to the etiology. In conclusion, hepatic overexpression of PKR and reduced expression of RNase L inhibitor seem to contribute to the anti-HCV mechanism characteristically.
...
PMID:Intrahepatic mRNA expression of interferon-inducible antiviral genes in liver diseases: dsRNA-dependent protein kinase overexpression and RNase L inhibitor suppression in chronic hepatitis C. 1105 60

Recently, mutations in the beta-catenin gene in hepatocellular carcinoma (HCC) have been reported: approximately 20% of HCCs had activating mutations at the glycogen synthase kinase 3beta phosphorylation sites within the exon 3 of the beta-catenin gene. However, changes in the level of the beta-catenin protein in HCC have not been well studied. We examined, by Western blotting, the expression level of the beta-catenin protein in cancerous tissues in comparison with that in adjacent non-cancerous tissues obtained from 32 cases of HCC with hepatitis C. An increase in the beta-catenin protein level in cancerous tissue compared to that in adjacent non-cancerous tissue was found in 15 (46.9%) of 32 cases of HCC. Mutation in exon 3 of the beta-catenin gene was found in six (18.8%) of the 32 cases, in five of which the beta-catenin protein level was increased. In total, beta-catenin aberration was found in 16 (50.0%) of 32 cases of HCC. It should be noted that beta-catenin aberration was also found in early HCC although it was observed chiefly in advanced HCCs. These results indicate that beta-catenin aberration is a frequent event in the development of HCC and may facilitate the development of HCC in the course of chronic hepatitis.
...
PMID:Frequent beta-catenin aberration in human hepatocellular carcinoma. 1128 85

Interferons (IFNs) induce an antiviral state in the cell through complex and indirect mechanisms, which culminate in a direct inhibition of viral replication and stimulation of the host adaptive responses. Viruses often counteract with elaborate strategies to interfere with the induction as well as action of IFN effector molecules. This evolutionary battle between viruses and IFN components is a subject of intense research aimed at understanding the immunopathogenesis of viruses and the molecular basis of IFN signaling and action. In the case with hepatitis C virus (HCV), this may have profound implications for the therapeutic use of recombinant IFN in treating chronic hepatitis C. Depending on the subtype of HCV, current IFN-based treatment regimens are effective for only a small subset of chronic hepatitis C patients. Thus, one of the Holy Grails in HCV research is to understand the mechanisms by which the virus may evade IFN antiviral surveillance and establish persistent infection, which may eventually provide insights into new avenues for better antiviral therapy. Despite the lack of an efficient tissue culture system and an appropriate animal model for HCV infection, several mechanisms have been proposed based on clinical studies and in vitro experiments. This minireview focuses on the HCV NS5A nonstructural protein, which is implicated in playing a role in HCV tolerance to IFN treatment, possibly in part through its ability to inhibit the cellular IFN-induced PKR protein kinase.
...
PMID:How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A. 1135 62

Mammalian cell cycle progression is regulated by the combined action of cyclins/cyclin-dependent kinases (CDKs) and CDK inhibitors. Abnormal expression as well as interaction of these proteins may result in malignant transformation of cells. To further address the role of these cell cycle proteins in hepatocellular carcinomas, we analyzed the expression of cyclin E and CDK2. A panel of livers with human hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis were used as a human experimental system. The inbred LEC (Long-Evans with a cinnamon-like coat color) rats were used as an animal experimental HCC model. Immunohistochemical staining of serial paraffin sections was performed using antibodies to cyclin E and CDK2. The results showed that cyclin E and CDK2 were concurrently overexpressed in hepatocellular carcinomas both in human and rat livers. Western blot analysis and CDK2 kinase assay demonstrated expression levels of cyclin E and CDK2 and CDK2 kinase activity, respectively, and both were shown to increase along with the development of hepatocellular carcinomas. Analysis of the correlation between expression of cyclin E and CDK2 and clinicopathological parameters revealed a significant correlation between expression of cyclin E and tumor grade (P=0.013), and PCNA index (P=0.006) as well as CDK2 expression (P=0.015). Overexpression of CDK2 tended to be associated with poorly differentiated HCCs. The results suggest that overexpression of cyclin E and CDK2 plays an important role in the development of hepatocellular carcinoma.
...
PMID:Overexpression of cyclin E and cyclin-dependent kinase 2 is correlated with development of hepatocellular carcinomas. 1147 Jun 26

Two genomic regions of hepatitis C virus (HCV), the interferon sensitivity-determining region (ISDR) of the non-structural 5A gene (NS5A) and the protein kinase-RNA activated (PKR)-eukariotic transcription factor (eIF2-alpha) phosphorylation homology domain (PePHD) of the structural E2 gene, interact in vitro with the interferon-inducible cellular PKR protein kinase. Mutations within these regions might, therefore, influence the response to interferon therapy. Viral load at baseline and sequence heterogeneity of HCV in NS5A and E2 regions was studied in 74 HCV-1b and in 12 HCV-3a infected patients with chronic hepatitis C who were treated with interferon. As previously reported by us, in a smaller series of patients in which the ISDR region was analyzed [Saiz et al. (1998) Journal Infectious Diseases 177:839-847], in the present study a low viral load and a high number of amino acid mutations within the ISDR, but not within the PePHD region, were significantly associated with long-term response to interferon among HCV-1b infected patients. No relationship between these viral features and response to therapy was disclosed in patients infected with HCV-3a.
...
PMID:Influence of the genetic heterogeneity of the ISDR and PePHD regions of hepatitis C virus on the response to interferon therapy in chronic hepatitis C. 1150 41

Human hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which often results in liver cirrhosis and hepatocellular carcinoma. The HCV RNA genome codes for at least ten proteins. The HCV non-structural protein 5A (NS5A) has generated considerable interest due to its effect on interferon sensitivity via binding and inactivating the cellular protein kinase, PKR. It has been shown that NS5A engages in the endoplasmic reticulum (ER)-nucleus signal transduction pathway. The expression of NS5A in the ER induces an ER stress ultimately leading to the activation of STAT-3 and NF-kappaB. This pathway is sensitive to inhibitors of Ca(2+) uptake in the mitochondria (ruthenium red), Ca(2+) chelators (TMB-8, EGTA-AM), and antioxidants (PDTC, NAC, Mn-SOD). The inhibitory effect of protein tyrosine kinase (PTK) inhibitors indicates the involvement of PTK in NF-kappaB activation by NS5A. This implicates an alternate pathway of NF-kappaB activation by NS5A. The actions of NS5A have also been studied in the context of an HCV subgenomic replicon inducing a similar intracellular event. Thus, activation of NF-kappaB leads to the induction of cellular genes, which are largely antiapoptotic in function. These studies suggest a potential function of NS5A in inducing chronic liver disease and hepatocellular carcinoma associated with HCV infection.
...
PMID:Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3. 1241 55

Recently, the envelope protein 2 (E2) of hepatitis C virus (HCV) was reported to interact with double stranded RNA-dependent protein kinase (PKR) through an element homologous to the phosphorylation site of PKR and its target, eukaryotic translation initiation factor (eIF) 2alpha (PKR-eIF2alpha phosphorylation homology domain: PePHD). Inhibition of the kinase activity of PKR by this interaction was postulated as a mechanism for the resistance to interferon (IFN) therapy. The aim of this study was to clarify whether the variation of PePHD amino acid sequences affects IFN efficacy in Japanese population. Amino acid sequences of PePHD (aa. 659-670 in genotype1b, aa. 663-674 in genotype 2a and 2b) were determined in randomly selected 112 patients with chronic hepatitis C (genotype 1b; 83 patients, 2a; 14 patients, 2b; 15 patients) prior to IFN monotheray. In 21 out of the 23 genotype 1b sustained responders (SR) (91%) and 55 out of the 60 non-SR (92%), PePHD sequences were identical to that of the HCV-1b consensus sequence. Only two SR showed one amino acid substitution in PePHD, and five non-SR showed amino acid substitutions in PePHD. Among 14 genotype 2a patients, only two SR had one amino acid substitution comparing to the consensus HCV-2a sequence. Likely, only one SR had an amino acid substitution in PePHD among 15 genotype 2b patients. In conclusion, our study revealed no clinical relationship between the amino acid sequence of PePHD and the outcome of IFN therapy. PePHD polymorphism was not suggested to play a role in predicting IFN efficacy.
...
PMID:Amino acid substitutions in PKR-eIF2 phosphorylation homology domain (PePHD) of hepatitis C virus E2 protein in genotype 2a/2b and 1b in Japan and interferon efficacy. 1296 25


1 2 3 Next >>

---