Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hepatitis C virus (HCV) core protein is believed to be one of viral proteins that are capable of preventing virus-infected cell death upon various stimuli. But, the effect of the HCV core protein on apoptosis that is induced by various stimuli is contradictory. We examined the possibility that the HCV core protein affects the ceramide-induced cell death in cells expressing the HCV core protein through the sphingomyelin pathway. Cell death that is induced by C(2)-ceramide and bacterial sphingomyelinase was analyzed in 293 cells that constitutively expressed the HCV core protein and compared with 293 cells that were stably transfected only with the expression vector. The HCV core protein inhibited the cell death that was induced by these reagents. The protective effects of the HCV core protein on ceramide-induced cell death were reflected by the reduced expression of p21(WAF1/Cip1/Sid1) and the sustained expression of the Bcl-2 protein in the HCV core-expressing cells with respect to the vector-transfected cells. These results suggest that the HCV core protein in 293 cells plays a role in the modulation of the apoptotic response that is induced by ceramide. Also, the ability of the HCV core protein to suppress apoptosis might have important implications in understanding the pathogenesis of the HCV infection.
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PMID:Suppression of ceramide-induced cell death by hepatitis C virus core protein. 1546 95

The hepatitis C virus (HCV) core protein plays important roles in hepatocarcinogenesis through modulation of cellular proliferation, apoptosis, and immunological responses. The roles of core protein in apoptosis have been conflicting; both proapoptotic and anti-apoptotic roles have been reported from different experimental conditions. Nonetheless, the overcoming apoptosis is a key molecular event to development of hepatocellular carcinoma. We investigated whether the HCV core-expressing cells are susceptible to apoptosis after cellular stress. Furthermore, we focused on the possibility that the presence of mutant p53 can render cells resistant to apoptosis. Our data clearly indicated that core-expressing cells showed increased apoptotic cell death through caspase-3 activation pathways after genotoxic stress without modulation of Bcl-2 family proteins. However, core-expressing cells, when transiently transfected with mutant p53, showed markedly increased resistance upon apoptosis after genotoxic stress. Thus, our data suggest that even though HCV core-expressing cells are susceptible to apoptosis after genotoxic stress, cells are resistant to apoptosis under mutant p53, implying a functional abnormality of p53 giving a chance to overcome apoptosis and ultimately cells develop into hepatocellular cell carcinoma.
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PMID:Modulation of cell death sensitivity by mutant p53 in HCV core-expressing cells. 1570 41

Hepatitis C virus (HCV) core protein has multifunctional activities. We have previously reported that the core protein of HCV immortalizes primary human hepatocytes, which may relate to multistage hepatocarcinogenic events. These immortalized human hepatocytes (IHH) served as a model to study the mechanism of HCV core protein-mediated cell growth regulation. Inhibition of core protein expression in earlier stages after hepatocyte immortalization leads to the induction of apoptosis. Here, we have observed that introduction of antisense core (AS-Core) sequences for inhibition of core protein expression enhanced the expression of E2F1 and p53 levels in early passage IHH. Inhibition of core protein expression also altered the expression level of Bcl-2 family proteins, displaying an increase of the proapoptotic Bax and a decrease in the level of the anti-apoptotic Bcl-xL proteins. These alterations, however, did not result in the release of cytochrome c from the mitochondria. Apaf-1 is frequently deregulated under various pathologic conditions, and examination of AS-Core-expressing apoptotic cells indicated a significant increase in the level of Apaf-1, which coincided with caspase-9 activation. Knockdown of Apaf-1 or the transcriptional regulatory proteins, E2F1 or p53, by small interfering RNA (siRNA) duplexes inhibited the activation of caspase-9 and enhanced cell viability in AS-Core-expressing cells. These findings may contribute to the understanding of the pathophysiology of HCV core protein-mediated hepatocyte growth regulation and disease progression.
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PMID:Inhibition of hepatitis C virus core protein expression in immortalized human hepatocytes induces cytochrome c-independent increase in Apaf-1 and caspase-9 activation for cell death. 1589 61

Infection with HCV can be associated with B-cell non-Hodgkin lymphoma. Polymerase chain reaction (PCR) amplification assays for Bcl-2/IgH rearrangement were performed on nucleic acids extracted from portal tract inflammatory infiltrates, isolated with laser capture microdissection (LCM), from liver biopsy sections of 16 hepatitis C virus (HCV)-infected patients with and without extrahepatic B cell-related disorders. Results were compared with total DNA extracted from core liver biopsy specimens and from peripheral blood mononuclear cells (PBMCs). We failed to demonstrate specific Bcl-2/IgH amplicons either in liver tissue or in PBMCs in all patients of the current series. Multiple PCR assays for variable diversity joining (VDJ) IgH gene rearrangements were also performed in the liver compartment. Selective amplification compatible with mono or oligoclonal B cell clonotypes was demonstrated in 80% (6/8) and 25% (2/8) of patients with and without clinical evidence of B-cell disorders. V(H)1 and V(H)3 were the most represented V(H) families. In situ expression of Bcl-2 protein was carried out by immunohistochemistry on liver biopsy sections. Bcl-2 protein was detected in 2 (12.5%) patients who did not associate extrahepatic disorders. In conclusion, current data support the concept that production of IgH gene rearrangements is not associated with Bcl-2/IgH chromosomal translocation in hepatic compartment. Liver overexpression of Bcl-2 protein may occur in at least a minor proportion of HCV-infected patients.
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PMID:HCV-associated B cell clonalities in the liver do not carry the t(14;18) chromosomal translocation. 1662 75

The liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and dietary antigens. Amongst the hepatitis viruses, only hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. Of the different antiviral defense systems employed by the tissue, apoptosis significantly contributes to the prevention of viral replication, dissemination, and persistence. Loss of tolerance to the liver autoantigens may result in autoimmune hepatitis (AIH). This review outlines the recent findings that highlight the role and mechanisms of apoptotic processes in the course of liver diseases. Among factors that contribute to liver pathology, we discuss the role of tumor necrosis factor (TNF)-alpha, HBx, ds-PKR, TRAIL, FasL, and IL-1alpha. Since TNF and FasL-induced hepatocyte apoptosis is implicated in a wide range of liver diseases, including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure, these items will be discussed in greater detail in this review. We also highlight some recent discoveries that pave the way for the development of new therapeutic strategies by protecting hepatocytes (for example by employing Bcl-2, Bcl-XL or A1/Bfl-1, IAPs, or synthetic caspase inhibitors), or by the induction of apoptosis in stellate cells. The assessment of the severity of liver disease, as well as monitoring of patients with chronic liver disease, remains a major challenge in clinical hepatology practice. Therefore, a separate chapter is devoted to a novel cytochrome c-based method useful for the diagnosis and monitoring of fulminant hepatitis.
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PMID:Apoptosis in liver diseases--detection and therapeutic applications. 1625 9

This study was designed to reveal whether the apoptosis induced in human hepatocellular carcinoma (HCC) cell lines by 5-fluorouracil (5-FU) could be enhanced by transfecting Bcl-2 small interfering RNA (siRNA). Bcl-2 siRNA and control siRNA were transfected into cells following treatment with or without 5-FU. Suppression of Bcl-2 expression was confirmed by Western blotting; cell viability was evaluated by MTS assay, and the occurrence of apoptosis in cells was evaluated by apoptosis assay. Expression of Bcl-2 protein after transfection of 20 nM Bcl-2 siRNA was significantly lower than that of control. Incubation of all cell lines with Bcl-2 siRNA reduced cell viability 96 h after 5-FU treatment compared with all other controls: Huh-7 (P < 0.01), Huh-7 with hepatitis C replicon (P < 0.01), HepG2 (P < 0.01), HLE (P < 0.05). Moreover, the proportion of apoptosis in control siRNA, Bcl-2 siRNA, control siRNA prior to 5-FU treatment, and Bcl-2 siRNA prior to 5-FU treatment groups were (4.6 +/- 2.3)%, (7.5 +/- 0.5)%, (6.0 +/- 2.1)%, and (19.5 +/- 0.86)%, respectively. The Bcl-2 siRNA prior to 5-FU treatment group showed the strongest effect of inducing apoptosis. In conclusion, the combination Bcl-2 siRNA and 5-FU might represent a new therapeutic option for HCC.
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PMID:Enhanced sensitivity of human hepatoma cells to 5-fluorouracil by small interfering RNA targeting Bcl-2. 1633 77

Hepatocellular carcinoma (HCC) is triggered by many factors including infection with hepatitis C virus (HCV). However, the molecular basis of the development of HCV-related HCC remains unknown. The present study was designed to reveal the interference of the HCV infection in HCC patients with a set of anti-apoptotic factors, and expression levels of some molecular markers between HCV-related HCC and non-HCV-related HCC. We have determined the plasma circulating levels of Bcl-2, TGF-betaI, VEGF, beta2-MG and immunohistochemistry staining of p53 in HCV-related HCC patients (n = 40) and compared them in relation to both HCV-free HCC patients (n = 37) and normal control group (n = 20). The present data do not distinctly predict a significant role of HCV infection on the circulating Bcl-2 protein since in both HCC and HCC/HCV groups a limited number of patients have high levels of Bcl-2. However, TGF-betaI expression is markedly decreased in all patients, particularly in HCC associated with HCV. Moreover, serum VEGF is significantly higher in HCC patients with or without HCV infection than in normal control. No significant difference, however, was found between HCV-infected and HCV-free groups. Presence of HCV is associated with a high incidence of Loss of Heterozygosity (LOH) at M6P/IGFIIr site compared to HCV-free patients. Although beta2-MG is markedly elevated in all patients, a significant increase was observed in the presence of HCV. Immunohistochemical positive total staining for p53 protein was detected in 32/77 (41.5%); HCC-positive HCV was 21/40 (52.2%), and HCC-negative HCV was 11/37 (29.73%). Collectively, in HCC patients, HCV infection does not affect the levels of Bcl-2 and VEGF. beta2-MG and LOH levels at the M6P/IGFIIr site were higher in the presence of HCV concomitant with a decrease in TGF-beta1. There was no significant correlation between p53 and stage of the disease or between p53 protein expression and clinicopathological manifestations.
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PMID:Molecular markers of hepatitis C virus-related hepatocellular carcinoma. 1662 84

Hepatitis C virus non-structural protein NS5A plays an important role in viral replication and various cellular events. To gain further insight into the function of NS5A, we screened a human fetal liver cDNA library for its interacting proteins using the yeast two-hybrid system. FKBP38, a 38 kDa immunosuppressant FK506-binding protein, was identified and its interaction with NS5A was confirmed by both in vitro and in vivo. The interaction was mapped to the amino acids 148-236 of NS5A containing a BH domain (Bcl-2 homology domain). Besides, both NS5A and FKBP38 were found to localize in mitochondria and endoplasmic reticulum. Moreover, NS5A stably expressing Huh7 hepatoma cells showed more resistance to apoptosis and such inhibition of apoptosis could specifically be abrogated by depletion of FKBP38 using RNA interference. These results indicate that HCV NS5A inhibits apoptosis through interaction with FKBP38.
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PMID:Hepatitis C virus non-structural protein NS5A interacts with FKBP38 and inhibits apoptosis in Huh7 hepatoma cells. 1684 19

In vitro and animal data suggest that hepatitis C virus (HCV) proteins might interfere with signal transducer and activator of transcription 3 (Stat3) signaling. It remains unknown whether Stat3 influences the apoptotic-proliferation balance and how this may relate to liver fibrosis progression in HCV-infected patients. We assessed Stat3 expression and DNA-binding as well as expression of its regulators protein inhibitor of activated Stat 3 (Pias3) and suppressor of cytokine signaling 3 (Socs3) in 65 HCV-infected livers at various stages of fibrosis progression. We then determined the level of expression of the proliferation markers cyclin D1 and proliferating cell nuclear antigen (PCNA) in conjunction with pro- and antiapoptotic markers Bax and Bcl-2 in the same liver samples. With the onset of fibrosis, Stat3 DNA-binding decreased and became almost undetectable in livers with bridging fibrosis or cirrhosis. Stat3 DNA-binding inversely correlated with Pias3 expression and Stat3-Pias3 interaction increased with the progression of fibrosis. Cyclin D1 and PCNA in hepatocytes decreased dramatically during fibrosis progression and levels highly correlated with Stat3 expression. In addition, an antiapoptotic profile due to upregulation of Bcl-2 principally in infiltrating inflammatory cells was observed with progressing fibrosis. In conclusion, fibrosis progression is characterized by a continuous decline in Stat3 DNA-binding activity related to overexpression and progressive interaction of Pias3-Stat3. The decrease in Stat3 activity correlated with reduced hepatocytes proliferation and a positive antiapoptotic balance in infiltrating inflammatory cells that are known mediators of cell damage in HCV.
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PMID:Role of signal transducer and activator of transcription 3 in liver fibrosis progression in chronic hepatitis C-infected patients. 1731 96

In recent years, the effects of hepatitis C virus (HCV) proteins on hepatocarcinogenesis have undergone intense investigations. The potentially oncogenic proteins include at least three HCV proteins: core (C) protein, NS3, and NS5A. Several authors indicated relationships between subcellular localization, concentration, a specific molecular form of the proteins (full length, truncated, phosphorylated), the presence of specific domains (the nuclear localization signal homologous to e.g. Bcl-2) and their effects on the mechanisms linked to oncogenesis. The involvement of all the proteins has been described as being in control of the cell cycle, through interactions with key proteins of the process (p53, p21, cyclins, proliferating cell nuclear antigen), transcription factors, proto-oncogenes, growth factors/cytokines and their receptors, and proteins linked to the apoptotic process. Untilnow, the involvement of the core protein of HCV in liver carcinogenesis is the most recognized. One of the most common proteins affected by HCV proteins is the p53 tumor-suppressor protein. The p21/WAF1 gene is a major target of p53, and the effect of HCV proteins on the gene is frequently considered in parallel. The results of studies on the effects of HCV proteins on the apoptotic process are controversial. This work summarizes the information collected thus far in the field of HCV molecular virology and principal intracellular signaling pathways in which HCV oncogenic proteins are involved.
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PMID:Role of hepatitis C virus proteins (C, NS3, NS5A) in hepatic oncogenesis. 1789


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