Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pien Tze Huang, a traditional Chinese medicine, has been extensively used as a therapeutic drug in the treatment of liver diseases. In this study, we have examined its ability to protect the liver from carbon tetrachloride (CCl4)-induced damage in the mouse. Histological observations revealed that CCl4 treatment induced extensive degenerative changes in the hepatocytes surrounding the central veins of the liver. However, these changes were much reduced by more than 28% in mice fed with 0.5 mg of Pien Tze Huang/g body weight/dose (3 doses over 36 hr) prior to CCl4 treatment. The effects of Pien Tze Huang were then further investigated in a hepatoma cell line. Flow analysis showed that it had no significant effects on cell proliferation. When the ability of Pien Tze Huang to influence various response elements of important signal transduction pathways was examined in the hepatoma cell line, it was found that Pien Tze Huang stimulated an increase in the response of AP1, CRE and NFkappaB responsive elements. The transcriptional factors of these responsive elements are known to play important roles in regulating cell death and survival. We thus postulate that the ability of Pien Tze Huang to protect the liver from damage is attained through its ability to modulate the activity of these important signal transduction pathways.
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PMID:Pien Tze Huang protects the liver against carbon tetrachloride-induced damage. 1253 Apr 69

Arsenic (As) contamination of drinking water is considered a principal environmental health threat throughout the world. Chronic intake is associated with an increased risk of cancer, diabetes, and cardiovascular disease, and recent studies suggest increased health risks at levels as low as 5-10 ppb. We report here that 0.05-1 microM (6-120 ppb) As showed stimulatory effects on glucocorticoid receptor (GR)-mediated gene activation in rat EDR3 hepatoma cells of both the endogenous tyrosine aminotransferase (TAT) gene and the reporter genes containing TAT glucocorticoid response elements. At slightly higher concentrations (1-3 microM), the effects of As became inhibitory. Thus, over this narrow concentration range, the effects of As changed from a 2- to 4-fold stimulation to a greater than 2-fold suppression in activity. Interestingly, the inhibitory effect of GR on both AP1- and NF-kappa B-mediated gene activation was not affected by As. The magnitude of GR stimulation and inhibition by As was highly dependent on the cellular level of hormone-activated GR. Mutational deletion studies indicated that the central DNA binding domain (DBD) of GR is the minimal region required for the As effect and does not require free sulfhydryls. Point mutations located within the DBD that have known structural consequences significantly altered the GR response to As. In particular, point mutations in the DBD that confer a DNA-bound GR confirmation abolished the low dose As stimulatory effect but enhanced the inhibitory response, further indicating that the DBD is important for mediating these As effects.
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PMID:Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression: complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain. 1531 Feb 38

Cytochrome P450 2E1 (CYP2E1) gene expression is known to be induced by interleukin-4 (IL4) and repressed by inflammatory cytokines, such as interleukin-1beta3 (IL1beta3) in human hepatocytes. The mechanisms involved in these transcriptional regulations remain elusive. In order to study these mechanisms, various constructs of the human CYP2E1 promoter were prepared and transfected into the human HepG2 hepatoma cell line. Our findings revealed that an IL4-responsive region of 128bp (-671/-544) was required to mediate induction by IL4. IL1beta caused moderate but significant decrease of the promoter activity, which was abolished when the two cytokines were combined. The IL1beta inhibitory effect is mediated through a regulatory sequence independent of that of IL4. Furthermore, by using specific signaling pathway inhibitors, we demonstrated that IL4 activation required protein kinase C (PKC) activation. In addition, our results suggest that induction by IL4 was not dependent on a single binding site but rather on a complex region which includes putative binding sites for signal transducer and activator of transcription (STAT)6, activator protein (AP)-1, nuclear factor kappa-B (NFkappaB), nuclear factor of activated T cells (NFAT) and CCAAT enhancer binding protein (C/EBP). Electrophoretic mobility shift assays suggest that AP1 and NFAT transcription factors are able to bind to three sites in the IL4-responsive region.
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PMID:Determination of interleukin-4-responsive region in the human cytochrome P450 2E1 gene promoter. 1534 27

Overexpression of platelet-derived growth factor A-chain (PDGF-A) is clearly linked to autocrine and paracrine stimulation of malignant growth in many human cancers. We have shown previously that PDGF-A overexpression in choriocarcinoma, hepatoma and lung carcinoma cell lines is driven by the activity of a 66 bp enhancer element (ACE66) located approximately 7 kb upstream of the PDGF-A transcription start site. In this study, the ACE66 element is shown to be activated in JEG-3 choriocarcinoma cells through synergistic interactions between consensus DNA motifs for binding of vitamin D receptor, AP1 and ELK1. Binding of the vitamin D/retinoid-X receptor (VDR/RXRalpha) heterodimer to the ACE66 element was reconstituted in vitro with recombinant VDR/RXRalpha and with JEG-3 nuclear extract, and was verified in living JEG-3 cells by chromatin immunoprecipitation analysis. Transcriptional activity of the ACE66 element, as well as occupancy of the element by VDR/RXRalpha, was shown to be independent of stimulation with the hormonal VDR ligand, 1,25-dihydroxyvitamin D3. The jun kinase pathway of mitogen-activated protein kinase (MAPK) signaling was shown to activate the ACE66 enhancer, most likely through activation of factors binding to the AP1 element. These results identify a novel mechanism of transcriptional enhancement involving ligand-independent activity of the VDR/RXR heterodimer and MAPK signaling pathways that appears to play an important role in the overexpression of PDGF in many different settings of human malignancy.
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PMID:A 5'-distal enhanceosome in the PDGF-A gene is activated in choriocarcinoma cells via ligand-independent binding of vitamin D receptor and constitutive jun kinase signaling. 1582 77

Ferritin is the major intracellular iron storage protein that sequesters excess free iron to minimize generation of iron-catalysed reactive oxygen species. We previously demonstrated that expression of ferritin heavy chain (ferritin H) was induced by pro-oxidants, which is a part of cellular antioxidant response to protect cells from oxidative damage. In this study, we have identified that the antioxidant/electrophile response element (ARE) located 4.5 kb upstream to the human ferritin H transcription initiation site is responsible for the oxidant response. The human ferritin H ARE comprises two copies of bidirectional AP1 motifs. Mutations in each AP1 motif significantly impaired protein binding and the function of the ARE, indicating that both of the AP1 motifs are required for pro-oxidant-mediated activation of the ferritin H gene. We identified that JunD, an AP1 family basic-leucine zipper (bZip) transcription factor, is one of the ferritin H ARE binding proteins and activates ferritin H transcription in HepG2 hepatocarcinoma cells. Gel retardation assay demonstrated that H2O2 (hydrogen peroxide) or t-BHQ (tert-butylhydroquinone) treatment increased total protein binding as well as JunD binding to the ferritin H ARE. Chromatin immunoprecipitation assay showed that H2O2 treatment induced JunD binding to the ferritin H ARE. Both H2O2 and t-BHQ induced phosphorylation of JunD at Ser-100, an activated form of JunD. Furthermore, overexpression of JunD induced endogenous ferritin H protein synthesis. Since JunD has recently been demonstrated to protect cells from several stress stimuli including oxidative stress, these results suggest that, in addition to NFE2-related factor 2 (Nrf2) as a major ARE regulatory protein, JunD is another ARE regulatory protein for transcriptional activation of the human ferritin H gene and probably other antioxidant genes containing the conserved ARE sequences by which JunD may confer cytoprotection during oxidative stress.
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PMID:JunD activates transcription of the human ferritin H gene through an antioxidant response element during oxidative stress. 1600 20

Genomic PCR reactions were performed to isolate gene sequences of tilapia metallothionein (tiMT) from Oreochromis mossambicus and Oreochromis aureus. Two AP1 binding sites, four metal responsive elements, and a TATA box are the major cis-acting elements identified in the 800-bp 5' flanking region of the tiMTs obtained in this study. The tiMT gene promoter cloned from O. aureus was characterized in vitro using PLHC-1 cell-line, a hepatocellular carcinoma of a desert topminnow (Poecciliopsis lucida), following the administrations of Cd2+, Co2+, Cu2+, Ni2+, Pb2+ and Zn2+. Only Cd2+, Pb2+ and Zn2+ were able to induce the transcription of tiMT gene promoter in PLHC-1 cells in a dose-dependent manner. Zn2+ had the highest fold induction of tiMT gene promoter activity. Deletion mutants were tested for their abilities to drive the transcription of reporter gene following Cd2+ and Zn2+ administrations. However, Cu2+ and Ni2+ also induced the production of hepatic MT mRNA in vivo. Northern blot analysis showed that liver gave the highest fold induction of MT gene expression following the administration of heavy metal ions. These data indicated that hepatic MT mRNA level in tilapia is a potential sensitive biomarker of exposure to various metal ions including Cu2+, Cd2+, Ni2+, Pb2+, Hg2+ and Zn2+ ions.
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PMID:Tilapia metallothionein genes: PCR-cloning and gene expression studies. 1630 56

Caspase-8 is frequently mutated or silenced in several tumors including hepatocellular carcinomas (HCC) thereby potentially contributing to chemoresistance. The aim of our present study was to evaluate if chemotherapeutic drugs may mediate their effects through up-regulation of caspase-8 gene transcription. Huh7 hepatoma cells were transfected with a caspase-8 promoter construct fused to a luciferase reporter gene followed by stimulation with a subset of different chemotherapeutic drugs. Several drugs slightly induced caspase-8 promoter activity. However, strong caspase-8 promoter induction was found after Mitomycin C (MMC) treatment and this correlated with an increase in endogenous caspase-8 mRNA expression. Further molecular analysis demonstrated that MMC controls caspase-8 transcription via a c-jun/AP1 site located in the promoter in close proximity to the transcription start site. Inactivation of this c-jun/AP1 site using a dominant-negative c-jun adenovirus or site-directed mutagenesis inhibited MMC-dependent promoter induction. MMC treatment resulted in higher caspase-8 enzymatic activity and apoptosis and could be synergistically enhanced by co-stimulation with interferon-alpha (IFNalpha) via independent transcriptional mechanisms. In summary MMC controls caspase-8 expression via a c-jun/AP1 element in its promoter region. MMC-induced up-regulation of caspase-8 triggers apoptosis in target cells which can be further enhanced by IFNalpha. Therefore these findings also provide a potential new therapeutic approach to treat cancer cells.
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PMID:Molecular mechanism of Mitomycin C-dependent caspase-8 regulation: implications for apoptosis and synergism with interferon-alpha signalling. 1792 91

Circadian clocks are self-sustained biochemical oscillators that autonomously generate a near-24 h cycle in the absence of external signals. The process of synchronization to the environment involves the transcriptional activation of several genes. Photic input signals from the retina are transduced via the retinohypothalamic tract to the central pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. It is known that cells of peripheral organs possess similar molecular organizations, but the signal transductional pathways lack direct light entrainment. It has been assumed that the adaptation of peripheral organs to the SCN phase is achieved by the alternate usage of promoter elements. This question has been addressed by characterizing the signal transductional pathways regulating human Period-1 gene expression in human hepatoma cells (HuH-7). Plasmids coding for key modulators of circadian rhythm, hCLOCK, hBMAL1, and hCRY2 were used to analyze the activation of a human period-1 promoter luciferase (hPER1-luc) construct. Beside classical CLOCK/BMAL1 activation, hPER1-luc was also inducible by the overexpression of the catalytic subunit of PKA (Calpha). The cotransfection of dominant negative constructs to c-FOS, CREB, PKA, and C/EBP were used to characterize both regulatory pathways. It was found that hCLOCK/hBMAL1-mediated hPER1 activation was influenced by AP1, but not significantly by other regulators. Conversely, PKA-induced activation of hPER1 was reduced by the inhibition of CREB and the CCAAT-box binding protein C/EBP, but not by AP1. The present findings imply that CLOCK/BMAL1-mediated activation of hPER1 by AP1 and E-Box elements is distinct from peripheral transcriptional modulation via cAMP-induced CREB and C/EBP.
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PMID:Activation of human period-1 by PKA or CLOCK/BMAL1 is conferred by separate signal transduction pathways. 1799 37

Transforming growth factor-beta1 (TGF-beta1) is a multi-functional cytokine involved in the regulation of cell proliferation, differentiation and extracellular matrix formation. In search for novel genes mediating the TGF-beta1 function at downstream signaling, we performed a cDNA microarray analysis and identified 60 genes whose expression is regulated by TGF-beta1 in the liver cancer cell line PLC/PRF/5. Among them, we report here lysyl oxidase like 4 (LOXL4) as a novel target of TGF-beta1 signaling, and provide experimental evidence for its expression regulation and function. LOXL4 was found to be the only member of LOX family whose expression is induced by TGF-beta1 in hepatoma cells. Deletion mapping of the LOXL4 promoter indicated that the TGF-beta1 regulation of LOXL4 expression is mediated through the binding of AP1 transcription factor to a conserved region of the promoter. This was confirmed by the chromatin immunoprecipitation assay that captured c-Fos-bound chromatin from TGF-beta1-treated cells. Forced expression of LOXL4 in PLC/PRF/5 cells resulted in inhibition of cell motility through Matrigel in the presence of TGF-beta1 treatment. In parallel, LOXL4 suppressed the expression of laminins and alpha3 integrin and the activity of MMP2. These results suggest that LOXL4 may function as a negative feedback regulator of TGF-beta1 in cell invasion by inhibiting the metabolism of extracellular matrix (ECM) components.
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PMID:Lysyl oxidase like 4, a novel target gene of TGF-beta1 signaling, can negatively regulate TGF-beta1-induced cell motility in PLC/PRF/5 hepatoma cells. 1858 5

Chemical carcinogens may cause a multitude of effects inside cells, thereby affecting transcript levels of genes by direct activation of transcription factors (TF) or indirectly through the formation of DNA damage. As the temporal profiles of these responses may be profoundly different, examining time-dependent changes may provide new insights in TF networks related to cellular responses to chemical carcinogens. Therefore, we investigated in human hepatoma cells gene expression changes caused by benzo[a]pyrene at 12 time points after exposure, in relation to DNA adduct and cell cycle. Temporal profiles for functional gene sets demonstrate both early and late effects in up- and downregulation of relevant gene sets involved in cell cycle, apoptosis, DNA repair, and metabolism of amino acids and lipids. Many significant transcription regulation networks appeared to be around TF that are proto-oncogenes or tumor suppressor genes. The time series analysis tool Short Time-series Expression Miner (STEM) was used to identify time-dependent correlation of pathways, gene sets, TF networks, and biological parameters. Most correlations are with DNA adduct levels, which is an early response, and less with the later responses on G1 and S phase cells. The majority of the modulated genes in the Reactome pathways can be regulated by several of these TF, e.g., 73% by nuclear factor-kappa B and 34-42% by c-MYC, SRF, AP1, and E2F1. All these TF can also regulate one or more of the others. Our data indicate that a complex network of a few TF is responsible for the majority of the transcriptional changes induced by BaP. This network hardly changes over time, despite that the transcriptional profiles clearly alter, suggesting that also other regulatory mechanisms are involved.
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PMID:Time series analysis of benzo[A]pyrene-induced transcriptome changes suggests that a network of transcription factors regulates the effects on functional gene sets. 2062 95


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