Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The family Flaviviridae contains three genera: Hepacivirus, Flavivirus, and Pestivirus. Worldwide, more than 170 million people are chronically infected with Hepatitis C virus and are at risk of developing cirrhosis and/or liver cancer. In addition, infections with arthropod-borne flaviviruses (such as dengue fever, Japanese encephalitis, tick-borne encephalitis, St. Louis encephalitis, Murray Valley encephalitis, West Nile, and yellow fever viruses) are emerging throughout the world. The pestiviruses have a serious impact on livestock. Unfortunately, no specific antiviral therapy is available for the treatment or the prevention of infections with members of the Flaviviridae. Ongoing research has identified possible targets for inhibition, including binding of the virus to the cell, uptake of the virus into the cell, the internal ribosome entry site of hepaciviruses and pestiviruses, the capping mechanism of flaviviruses, the viral proteases, the viral RNA-dependent RNA polymerase, and the viral helicase. In light of recent developments, the prevalence of infections caused by these viruses, the disease spectrum, and the impact of infections, different strategies that could be pursued to specifically inhibit viral targets and animal models that are available to study the pathogenesis and antiviral strategies are reviewed.
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PMID:Perspectives for the treatment of infections with Flaviviridae. 1062 92

Histological features of primary liver cancer among atomic-bomb survivors and their relationship to hepatitis B (HBV) and C viral (HCV) infections are of special interest because of the increased risk of liver cancer in persons exposed to ionizing radiation and the high and increasing liver cancer rates in Japan and elsewhere. We conducted a pathology review of liver cancers occurring from 1958 to 1987 among subjects in the 120,321 member cohort of 1945 Hiroshima and Nagasaki residents. A panel of pathologists classified tumor histological types and defined accompanying cirrhotic changes of the liver. Archival tissue samples were assessed for HBV using pathology stains and PCR. Reverse transcriptase (RT) PCR was used to determine HCV status. We used unconditional logistic regression to compare 302 hepatocellular carcinoma (HCC) cases to 53 cholangiocarcinoma (CC) cases, adjusting for age, year of diagnosis, sex and viral status. Cirrhotic changes occurred significantly more often among HCC than CC cases (76% in HCC and 6% in CC). Compared to CC cases, HCC cases were 10.9 times more likely to be HBV-positive (95% confidence interval: 2.1-83.2) and 4.3 times more likely to be HCV-positive (95% confidence interval: 1.1-20.5). No significant differences were found between HCC and CC cases in radiation exposures. The predominance of HCC in the atomic-bomb survivors follows the background liver cancer pattern in Japan. Our findings suggest that HBV and HCV are involved in the pathogenesis of HCC with or without cirrhosis and are significantly less important in that of CC.
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PMID:Liver cancer in atomic-bomb survivors: histological characteristics and relationships to radiation and hepatitis B and C viruses. 1159 79

Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis. The World Health Organization estimates that 170 million people world-wide are infected with HCV; 70% of them will develop chronic hepatitis and 20-30% cirrhosis in 10-30 years. Of those with cirrhosis, an estimated 25-30% will develop liver cancer. Since the identification and molecular characterization of HCV in 1989, a variety of diagnostic tests based on the detection of hepatitis virus antibodies or HCV RNA in the serum have been developed. The enzyme-linked immunosorbent assays (ELISA 3) and the recombinant immunoblot assays (RIBA 2nd and 3rd generation) exhibit improved sensitivity and specificity for HCV antibodies. Qualitative and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) has allowed clinicians to track the natural history of HCV and to monitor the progress of therapy. This article reviews the state-of-the-art tests and assays developed for the diagnosis and management of HCV infection.
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PMID:[Diagnostic strategies in Hepatitis C virus infection]. 1209 56

The retinoblastoma tumor-suppressor protein (Rb) plays a critical role in controlling cellular proliferation and apoptosis by regulating E2F transcription factors. Rb is a key target of oncoproteins expressed by DNA tumor viruses, but RNA viruses are not known to regulate Rb function. Here, we show that Rb abundance is negatively regulated in cells containing replicating genomic RNA from hepatitis C virus, a human virus strongly associated with hepatocellular carcinoma. The viral RNA-dependent RNA polymerase NS5B forms a complex with Rb, targeting it for degradation and resulting in reduction of Rb abundance, activation of E2F-responsive promoters, and cell proliferation. NS5B contains a conserved Leu-x-Cys/Asn-x-Asp motif that is homologous to Rb-binding domains in the oncoproteins of DNA viruses. This domain overlaps the polymerase active site, and mutations within it abrogate Rb binding and reverse the effects of NS5B on E2F promoter activation and cell proliferation. These findings suggest a unique link between an oncogenic RNA virus implicated in the development of liver cancer and a critically important tumor-suppressor protein.
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PMID:Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. 1633 62

Hepatitis C virus (HCV) is a positive-strand RNA virus that frequently causes persistent infections and is uniquely associated with the development of hepatocellular carcinoma. While the mechanism(s) by which the virus promotes cancer are poorly defined, previous studies indicate that the HCV RNA-dependent RNA polymerase, nonstructural protein 5B (NS5B), forms a complex with the retinoblastoma tumor suppressor protein (pRb), targeting it for degradation, activating E2F-responsive promoters, and stimulating cellular proliferation. Here, we describe the mechanism underlying pRb regulation by HCV and its relevance to HCV infection. We show that the abundance of pRb is strongly downregulated, and its normal nuclear localization altered to include a major cytoplasmic component, following infection of cultured hepatoma cells with either genotype 1a or 2a HCV. We further demonstrate that this is due to NS5B-dependent ubiquitination of pRb and its subsequent degradation via the proteasome. The NS5B-dependent ubiquitination of pRb requires the ubiquitin ligase activity of E6-associated protein (E6AP), as pRb abundance was restored by siRNA knockdown of E6AP or overexpression of a dominant-negative E6AP mutant in cells containing HCV RNA replicons. E6AP also forms a complex with pRb in an NS5B-dependent manner. These findings suggest a novel mechanism for the regulation of pRb in which the HCV NS5B protein traps pRb in the cytoplasm, and subsequently recruits E6AP to this complex in a process that leads to the ubiquitination of pRb. The disruption of pRb/E2F regulatory pathways in cells infected with HCV is likely to promote hepatocellular proliferation and chromosomal instability, factors important for the development of liver cancer.
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PMID:Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein. 1790 5

Myrtenal is a novel class of compound belongs to monoterpenes found predominantly in mint, pepper, etc., and it was shown to have excellent pharmacological activities against many diseases among which cancer is imperative. Hepatocellular carcinoma is a primary malignancy of the hepatocytes, which rapidly leads to death in short periods. The aim of this study was to investigate the possible therapeutic efficiency of myrtenal against diethylnitrosamine-induced experimental hepatocarcinogenesis by analyzing the key enzymes of carbohydrate metabolism, lysosomal and mitochondrial TCA cycle enzymes, and also the possible role of tumor suppressor protein p53, and scanning electron microscopic studies. The results revealed that myrtenal significantly ameliorated the altered enzymes of carbohydrate metabolism, lysosomal and mitochondrial enzymes, and interestingly the tumor suppressor protein p53 was found to be significantly accumulated in myrtenal-treated animals, which inevitably confirms that myrtenal has a prominent role in preventing the liver cancer during treatment. Furthermore, the antineoplastic property was well evidenced by the mRNA expression of p53 protein by the reverse-transcriptase polymerase chain reaction and immunoblot analysis. The observed anticancer property of myrtenal may be due to the involvement and expression of p53 and influence in the mitochondrial and lysosomal membrane integrity and also interference in the gluconeogenesis process of cancer cells. Our results suggest that myrtenal is very efficient and useful compound in the treatment of liver cancer in future.
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PMID:Myrtenal ameliorates diethylnitrosamine-induced hepatocarcinogenesis through the activation of tumor suppressor protein p53 and regulation of lysosomal and mitochondrial enzymes. 2243 21