UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hormonal regulatory elements within the phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) promoter region were mapped using a series of 5' deletions linked to the amino-3'-glycosyl phosphotransferase structural gene. These deletion mutants were stably transfected into the genome of FTO-2B hepatoma cells. A 47-base pair region of the PEPCK promoter was identified which was essential for stimulation by dibutyryl cAMP. A 12-base pair core sequence (CTTACGTCAGAG) within this region shows significant homology with sequences in four other cAMP-regulated genes. There are two glucocorticoid regulatory elements within the promoter, as well as an inhibitory element which depresses the level of basal gene transcription. The deletion of this inhibitory sequence prevents the induction of the chimeric gene by dexamethasone. The existence of the hormone regulatory domains within the PEPCK promoter was confirmed by attaching these elements upstream of the heterologous Herpes simplex virus thymidine kinase structural gene, containing its own promoter.
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PMID:Characterization of the phosphoenolpyruvate carboxykinase (GTP) promoter-regulatory region. II. Identification of cAMP and glucocorticoid regulatory domains. 301 3

We describe a human genomic clone containing the metallothionein (MT) IF and MT IG genes. Southern blot analysis and partial DNA sequence determinations show that these genes are organized in a head-to-head fashion and are located approximately 7.0 kilobases apart from each other. Sequence analysis shows that the MT IF gene contains three exons separated by two introns. All of the intron-exon junctions are defined by the GT-AG rule. The 5' flanking region shows the presence of a duplicated metal regulatory element (TGCGC CCGGCCC) important in heavy-metal induction of this gene and a sequence for its basal level expression (GCGGGGCGGGTGCAAAG). The 5' flanking region is also highly G + C rich (approximately 75%) and contains several GC boxes (GGGCGG), probably important in the binding of transcription factors. The TATAA box and the AATAAA sequence are represented by their variants, the TATCAA box and the AATTAA sequence, respectively. This gene is functional and inducible by heavy metals but not by dexamethasone in mouse LMTK- cells after its transfer on a plasmid containing the herpes simplex virus thymidine kinase gene. Further studies on various human cell lines show that this gene is not expressed in a splenic lymphoblastoid cell line (WI-L2) but is expressed in two hepatoma cell lines (Hep 3B2 and Hep G2) in response to cadmium, zinc, and copper. Dexamethasone appears to have no significant effect on its expression. The studies suggest that the MT IF gene shows cell-type-specific expression and is differentially regulated by heavy metals and glucocorticoids.
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PMID:Structure, organization, and regulation of human metallothionein IF gene: differential and cell-type-specific expression in response to heavy metals and glucocorticoids. 302 27

Sexually transmitted diseases (STDs) are diagnosed in 10 million patients per year in the United States. The infected individuals come from all walks of life and all age groups. They may present with either genital or nongenital signs and symptoms. Most individuals are treated as outpatients, but more than a quarter of a million hospital admissions for STDs are necessary each year. These numbers will rise precipitously as the number of AIDS cases increases. More than 10,000 deaths per year are caused by STDs, primarily because of AIDS, cervical carcinoma, and hepatitis B induced cirrhosis and hepatoma. Physicians must become highly skilled in the diagnosis and treatment of the common STDs caused by herpes simplex virus, Neisseria gonorrhoeae, and Chlamydia trachomatis. Simple office microscopic skills are needed for the diagnosis of vaginitis, cervicitis, and urethritis, and all physicians should be encouraged to develop these skills. Physicians will need to keep abreast of the rapidly evolving changes in the diagnosis and treatment of STDs.
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PMID:The office approach to the sexually transmitted diseases: Part I. 362 20

cAMP stimulates the transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) in rat liver. We have investigated the nucleotide sequences required for regulation of PEPCK gene expression by cAMP. A chimeric gene was constructed in which a 620-base pair fragment of the 5'-end of the PEPCK gene (including 547 base pairs of 5'-flanking sequence) was ligated to the herpes simplex virus thymidine kinase (TK) structural gene. The PEPCK promoter fragment was introduced either in the proper orientation for transcription of the TK gene or in the opposite orientation. These fusion genes and the parent vector, pOPF, which contains the intact TK gene, were transfected individually into TK-deficient FTO-2B rat hepatoma cells. FTO-2B cells contain an active endogenous PEPCK gene which is stimulated by cAMP. Cells were selected in HAT medium and grown either as mass cell cultures or as individual clones. Dibutyryl cyclic AMP (Bt2cAMP) plus theophylline (16 h) stimulated TK activity 1.6-6.1-fold in cell lines transfected with the PEPCK-TK fusion gene containing the PEPCK promoter fragment in the correct orientation. However, the intact TK gene was not induced by Bt2cAMP after transfection, nor was there any expression of the PEPCK-TK fusion gene in cells which contained the PEPCK promoter fragment in the wrong transcriptional orientation. Bt2cAMP also increased the levels of TK mRNA in cells transfected with the PEPCK-TK fusion gene, but not in cells transfected with the intact TK gene. The chimeric PEPCK-TK mRNA initiated at the PEPCK start site, as determined by S1 nuclease mapping. There was no relationship between the number of copies of the PEPCK-TK gene integrated in the various cell lines and either the basal level of TK activity or its inducibility of Bt2cAMP.
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PMID:Identification of a cAMP regulatory region in the gene for rat cytosolic phosphoenolpyruvate carboxykinase (GTP). Use of chimeric genes transfected into hepatoma cells. 609 Apr 58

The immune system has evolved under Darwinian pressures as a defence against ubiquitous viruses. Immune surveillance against viral antigens protects the normal host. Individuals with inherited or acquired immune-deficiency disorders can become vulnerable to ubiquitous viruses and neoplasms can ensue, such as B-cell lymphoma, hepatocellular carcinoma, squamous-cell carcinoma, Kaposi's sarcoma, and carcinoma of the penis and uterine cervix. Immunodeficiency permits Epstein-Barr virus, hepatitis B virus, papillomavirus, herpes simplex virus, and cytomegalovirus to induce sustained target-cell proliferation. Each virus selects specific cellular targets bearing viral receptors and the infection leads to proliferation of the target cells rather than lysis. Various co-factors, including nutrition, exposure to tumour-promoting agents, parasitic infection, and ultraviolet light, may promote carcinogenesis. Depending on the type and severity of the immune deficiency, gradual proliferation may lead to evolution of a malignant clone. Conversion of polyclonal virally infected proliferating cells to give monoclonal malignancy is probably due to specific cytogenetic rearrangements which allow oncogene activation and endow an altered tumour cell with selective growth advantages over normal diploid cells. Prevention of viral oncogenesis may be possible by treatment of immune-deficient individuals with premalignant disorders. Immunotherapy and antiviral therapy may prevent progression of viral-induced proliferation to malignancy. The purpose of this paper is to discuss and evaluate the role of immune deficiency and viruses in the induction of malignancies commonly occurring in Africans residing in sub-Saharan Africa (Purtilo, 1976). The types of malignancies commonly occurring in this region are believed to be due to ubiquitous viruses. A failure of immune surveillance mechanisms to recognize viral antigens and abrogate proliferation of infected target cells predisposes to malignancy by increasing the chance of a proliferating cell undergoing a cytogenetic or molecular alteration which endows it with malignant characteristics. The immunological surveillance hypothesis has been elaborated during this century by Ehrlich, Thomas, Burnet, and Schwartz (reviewed by Purtilo & Linder, 1983). This hypothesis rests on several assumptions: that neoplastic cells possess unique tumour antigens: tumour antigens provoke an immune response in the host; and the immune response is protective and eliminates the tumour.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Squamous-cell carcinoma, Kaposi's sarcoma and Burkitt's lymphoma are consequences of impaired immune surveillance of ubiquitous viruses in acquired immune deficiency syndrome, allograft recipients and tropical African patients. 610 Feb 88

The effect of herpes simplex virus type 2 (HSV-2) infection of hepatoma McA-RH7777 cells on the production of alpha-fetoprotein (AFP) and several other secreted plasma proteins was examined. Cells infected with HSV-2 were labeled with [35S]methionine for various times postinfection (p.i.). Culture media and intracellular extracts were immunoprecipitated with plasma protein antibodies and examined by polyacrylamide gel electrophoresis. The relative levels of AFP and several other plasma proteins decreased substantially in infected cells compared with mock-treated controls; however, the level of at least one secreted plasma protein was unchanged after infection and the level of another increased after infection. Hybridization analyses with AFP cDNA showed that AFP RNA decreased to 43 and 30% of controls at 3.5 and 6.5 hr p.i., respectively. These observations were supported by the results of cell-free translation of isolated poly(A)-containing RNA. HSV-2 proteins were not detectable at times p.i. when AFP synthesis, secretion, and mRNA levels were significantly diminished. No decrease in AFP levels was observed in cells infected with ultraviolet-irradiated virus. We conclude that HSV-2 infection of McA-RH7777 cells leads to a rapid decrease in synthesis and secretion of specific plasma proteins which is apparent, at least for AFP, at the level of mRNA. This shutoff is not common to all McA-RH7777 cell proteins and, although seen early after infection, most likely requires the expression of a virus gene(s).
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PMID:Rapid and selective shutoff of plasma protein production in herpes simplex virus type 2-infected hepatoma cells. 619 Mar 9

We have cloned circular unintegrated mouse mammary tumor virus (MMTV) DNA from infected rat hepatoma cells in bacteriophage lambda. Seven independent clones containing MMTV DNA of homogeneous length of 9 kb (five) or 10 kb (two) were identified. The five 9 kb clones had identical restriction maps consistent with that of 9 kb unintegrated DNA; the other two were aberrant. MMTV DNA inserts were purified, ligated and used for cotransfection of Ltk- cells together with a plasmid containing the thymidine kinase gene of herpes simplex virus. All Tk+ cell clones acquired new MMTV sequences and those transfected with the 9 kb MMTV DNA synthesized normal viral RNA and proteins. Viral gene expression was increased by the addition of dexamethasone.
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PMID:Cloned mouse mammary tumor virus DNA is biologically active in transfected mouse cells and its expression is stimulated by glucocorticoid hormones. 625 99

The cause of human cancer is probably multifactorial and the role of viruses is unclear. The study of retroviruses has led to the identification of oncogenes responsible for transformation and tumor induction. Human viruses associated with malignancies include the JC virus (associated with progressive multifocal leukoencephalopathy) and some adenoviruses. No human malignancies have been associated with the latter group. A number of herpes viruses of lower animals have been associated with malignancies and herpes simplex virus type 2 has been associated with carcinoma of the cervix and vulva. The Epstein-Barr virus has been associated with Burkitt's lymphoma and nasopharyngeal carcinoma. Some circumstantial evidence suggests that cytomegalovirus may be associated with Kaposi's sarcoma among homosexuals. The hepatitis B virus (HBV) has been associated with hepatocellular carcinoma. The fullfillment of Koch's postulates presents ethical problems regarding man and proving the viral etiology of human malignancy. Social experiments may elucidate some of these questions. An increase in venereal herpes should be associated with an increase in carcinoma of the cervix and use of the HBV vaccine in populations with high incidences of HBV carrier states should decrease the incidence of hepatocellular carcinoma. The investigation of the retroviruses though not establishing viruses as causing human malignancies at least will improve our understanding of the malignant process.
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PMID:Viruses and human cancer. 687 Jan 84

In the field of gene therapy using retroviral vectors, it appears impossible to introduce a foreign gene into all target cells. Therefore adjacent cell killing, the socalled bystander effect, caused by genetically modified cells provides therapeutic advantages for gene therapy against cancers. We retrovirally transduced the herpes simplex virus thymidine kinase (HSV-tk) gene into murine and rat hepatocellular carcinoma (HCC) cells. These HSV-tk gene-transduced HCC cells were cocultured with the corresponding parental cells in the presence of ganciclovir, at a concentration not at all cytotoxic to the parental cells. When parental HCC cells were cocultured with their HSV-tk gene-transduced counterparts at a high density at which most cells were in contact with one another, they were markedly eliminated. Conversely, when cocultured at a low density at which none of the cells were in contact, a weak but statistically significant bystander effect was observed. Addition of lysates of HSV-tk gene-transduced cells in the presence of ganciclovir did not cause and killing of parental cells. Furthermore, media conditioned by transduced cells with ganciclovir exhibited weak cytotoxic effects on parental cells. These results indicate that cell-cell contact plays a major causative role in the bystander effect and that minor contributors to this phenomenon are some cytotoxic substance released from transduced cells. Importantly, the bystander effect was induced in vivo as well as in vitro. When mixtures of transduced and untransduced HCC cells were implanted into the flank region of mice, intraperitoneal ganciclovir administration considerably inhibited tumor development, indicating the feasibility of gene therapy with HSV-tk gene and ganciclovir against HCC.
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PMID:Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma. 748 96

The alpha-fetoprotein (AFP) gene is normally expressed in fetal liver and transcriptionally silent in adult tissues, but can be abnormally reactivated in hepatocellular carcinoma (HCC). We linked 7.6 kb of 5'-flanking DNA from the mouse AFP gene to the herpes simplex virus (HSV) thymidine kinase gene (tk), and a line of transgenic mice was produced that expressed TK in a pattern similar to endogenous AFP. When these AFP/tk transgenic mice were crossed to another transgenic line that develops multifocal HCC due to expression of a SV40 large T-antigen transgene under regulation of the albumin promoter/enhancer complex, a significant delay of tumor progression could be achieved by administration of ganciclovir (GCV), a cytotoxic compound that is a substrate for phosphorylation by viral, but not mammalian, TK. Control animals carrying only the tk gene were unaffected by GCV treatment. These results illustrate the feasibility of prophylactic gene therapy for ablation of cancer, utilizing a strategy in which the tk gene is regulated by a promoter expected to be active only in tumor cells.
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PMID:Delayed morbidity and mortality of albumin/SV40 T-antigen transgenic mice after insertion of an alpha-fetoprotein/herpes virus thymidine kinase transgene and treatment with ganciclovir. 751 48

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