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)

We have recently identified an Ets element controlling over 90% of the basal expression of the human presenilin 1 (PS1) gene. We have also shown that Ets1 and Ets2 act as transactivators of the PS1 gene by cotransfection experiments in SK-N-SH neuronal cells. The PS1 gene is widely but differentially expressed across tissues and the expression in brain appears to be restricted to neurons. To gain further insight into the regulation of the gene we have examined the regulation of PS1 by 12-O-tetradecanoylphorbol 13-acetate (TPA). SK-N-SH neuronal cells were treated with 0.2 micro m TPA for 30 min to 24 h and the level of expression of the endogenous PS1 gene was measured by Northern blot analysis. A two- to threefold increase in the level of PS1 mRNA appeared 4-8 h after the addition of TPA. A similar increase in transcription activity was observed in nuclear run off experiments, indicating that the increased mRNA level results from an activation in the initiation of transcription of PS1. Consistently, TPA also increased the level of PS1 protein. No activation of the PS1 endogenous gene by TPA was observed in hepatoma HepG2 cells. Next we tested the effect of TPA on the expression of the PS1 promoter by transfecting fusion genes including various fragments of the PS1 promoter linked to a CAT reporter into SK-N-SH cells. TPA also stimulated the expression of the PS1CAT constructs. Generally wild type constructs -687/+178, -118/+178, -22/+178 including the short -35/+6 fragment showed a minor two- to threefold activation by TPA. Point mutations eliminating the -10 Ets motif or the -6 CREB/AP1 motif did not decrease the stimulation by TPA. Thus TPA appears to activate the transcription of the PS1 gene by a mechanism which does not require these elements.
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PMID:Activation of transcription of the human presenilin 1 gene by 12-O-tetradecanoylphorbol 13-acetate. 1244 85

Compound 5 (Cpd 5) or 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone, is an inhibitor of protein phosphatase Cdc25A and causes persistent activation of extracellular signal-regulated kinase (ERK) and cell growth inhibition. To study the mechanism(s) by which persistent ERK phosphorylation might induce cell growth inhibition, we used Cpd 5 as a tool to examine its effects on the activity of CREB (cAMP response element-binding protein) transcription factor in Hep3B human hepatoma cells. We found that CREB activity, including its DNA binding ability and phosphorylation on residue Ser-133, was strongly inhibited by Cpd 5, followed by suppression of CRE-mediated transcription of cyclin D1 and Bcl-2 genes. Cpd 5-mediated suppression of CREB phosphorylation and transcriptional activity was antagonized by mitogen-activated protein kinase kinase inhibitors PD 98059 and U-0126, implying that this inhibition of CREB activity was regulated at least in part by the ERK pathway. The phosphorylation of ribosomal S6 kinase (pp90(RSK)), a CREB kinase in response to mitogen stimulation, was also found to be inhibited by Cpd 5 action. This inhibition of pp90(RSK) phosphorylation is likely the result of its increased association with CREB-binding protein (CBP), which subsequently caused inhibition of CREB phosphorylation and activity. To support the hypothesis that Cpd 5 effects on Cdc25A inhibition with subsequent ERK activation could cause CREB inhibition, we examined the effects of Cdc25A inhibition without the use of Cpd 5. Hep3B cells were transfected with C430S Cdc25A mutant, and ERK was found to be phosphorylated in a constitutively activated manner, which was accompanied by decreased CREB phosphorylation and increased recruitment of CBP to pp90(RSK). These data provide evidence that CBP.RSK complex formation in response to persistent ERK phosphorylation by Cpd 5 down-regulates CREB activity, leading to inhibition of both cAMP response element-mediated gene expression and cell growth.
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PMID:Persistent ERK phosphorylation negatively regulates cAMP response element-binding protein (CREB) activity via recruitment of CREB-binding protein to pp90RSK. 1254 Aug 38

A common signature of many cancers is a high glucose catabolic rate frequently dependent on the overexpression of Type II hexokinase (HKII), a mitochondrial bound enzyme that also suppresses cell death. As the tumor HKII promoter plays a significant role in HKII overexpression, studies reported here were undertaken to identify both the major regions and transcription factors involved under tumor-like conditions. Reporter gene assays following transfection of hepatoma cells with decreasing segments of the HKII promoter traced its known strength to the proximal region (-281 to -35). Mutational analyses showed that in this short region GC boxes 1, 2, 5, and 6, a CCAAT box, an inverted CCAAT box, and CRE are involved in promoter activation. Other studies demonstrated binding of transcription factors Sp1, Sp2, and Sp3 to GC boxes 1 and 6, Sp1 and Sp2 to GC boxes 2 and 5, NF-Y to CCAAT boxes, and CREB, ATF1, and CREM to CRE. In addition, transfection studies involving Sp1, Sp2, Sp3, CREB, and NFY (dominant negative form) provided evidence that these proteins are promoter activators. Finally, alignment of available HK proximal promoters showed strong conservation only among HKII sequences. These findings implicate signaling pathways directed to a short segment of the proximal region of the HKII promoter as major contributors to HKII overexpression in many cancers.
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PMID:Glucose metabolism in cancer: importance of transcription factor-DNA interactions within a short segment of the proximal region og the type II hexokinase promoter. 1289 19

Despite the small size of its genome (3.2 kb) and having only four genes that are encoded within it, the hepatitis B virus (HBV) is one of the most successful viral pathogens in human history. It is estimated that there are about 350-400 million people worldwide who are chronically infected with HBV, and even with the extensive efforts that are being done with preventive vaccination, this malady still remains a clear and present danger to the public health. How is it possible that this small double-stranded DNA virus can escape and outfox the surveillance of the complex human immune system? One explanation is that HBV gene products play multiple roles in infections and throughout the viral life cycle so that the virus can effectively survive under various hostile circumstances. Indeed, the HBV DNA polymerase, for example, exerts several functions such as reverse transcription and RNA degradation, and the HBV X protein not only acts as a transcriptional activator, but it also interferes with the host cells' DNA repair mechanism as well as inducing apoptosis and controlling signal transduction. The HBV surface protein, which is encoded in the env gene, is another intriguing example of such multifunctionality. Thus, our present article overviews and summarizes the multifaceted role of this membrane protein as shown in 1) its role as a structural protein of the virus envelope; 2) its function as the viral ligand for interacting with the viral receptors on host cells; 3) its characteristics as an energy-independent transporter molecule that can mediate the nuclear accumulation of itself and other tagged molecules; 4) its role as a viral transactivator protein that can cause hepatocellular carcinoma; 5) its hypothetical function in viral apoptotic mimicry that results in host anti-inflammatory responses; and last 6) its immunostimulatory property by providing for strong and well-defined B- and T-cell epitopes. Understanding these various functions and the versatility of this single protein will help us decipher and understand the viral- and immuno-pathogenesis of HBV itself.
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PMID:[Hepatitis B virus surface antigen: a multifaceted protein]. 1561

The potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) induces activator protein-1 (AP-1) transcription factors, early response genes involved in a diverse set of transcriptional regulatory processes, and protein kinase C (PKC) activity. This work was designed to explore the signal transduction pathways involved in TPA regulation of 5-aminolevulinate synthase (ALAS) gene expression, the mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of heme biosynthesis. We have previously reported that TPA causes repression of ALAS gene, but the signaling pathways mediating this effect remain elusive. The present study investigates the role of different cascades often implicated in the propagation of phorbol ester signaling. To explore this, we combined the transient overexpression of regulatory proteins involved in these pathways and the use of small cell permeant inhibitors in human hepatoma HepG2 cells. In these experimental conditions, we analyzed TPA action upon endogenous ALAS mRNA levels, as well as the promoter activity of a fusion reporter construct, harboring the TPA-responsive region of ALAS gene driving chloramphenicol acetyl transferase gene expression. We demonstrated that the participation of alpha isoform of PKC, phosphatidylinositol 3-kinase (PI3K), extracellular-signal regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK) is crucial for the end point response. Remarkably, in this case, ERK activation is achieved in a Ras/Raf/MEK-independent manner. We also propose that p90RSK would be a convergent point between PI3K and ERK pathways. Furthermore, we elucidated the crosstalk among the components of the cascades taking part in TPA-mediated ALAS repression. Finally, by overexpression of a constitutively active p90RSK and the coactivator, cAMP-response element protein (CREB)-binding protein (CBP), we reinforced our previous model, that implies competition between AP-1 and CREB for CBP.
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PMID:Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways. 1579 41

Activation of extracellular signal-regulated protein kinase (ERK) triggers the biosynthesis of Egr-1, a zinc finger transcription factor. Likewise, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) strongly upregulates Egr-1 biosynthesis. Here, we have analyzed the genetic elements involved in the regulation of Egr-1 gene transcription by ERK and TPA in human hepatoma cells. Expression experiments using mitogen-activated protein kinase phosphatase-1 or a dominant-negative mutant of the ternary complex factor Elk-1 revealed that the distal cluster of serum response elements is essential in the TPA-induced enhancement of Egr-1 promoter activity, encompassing two independent TPA-responsive elements. The CRE in the proximal Egr-1 promoter plays, if anything, only a marginal role in TPA-induced stimulus-transcription coupling of the Egr-1 gene. The fact that Egr-1 promoter/reporter gene transcription is upregulated by a constitutively active CREB mutant indicates that the CRE couples other signaling cascades via CREB to the Egr-1 gene.
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PMID:Transcriptional activation of the Egr-1 gene mediated by tetradecanoylphorbol acetate and extracellular signal-regulated protein kinase. 1591 Jul 36

The role of cyclic adenosine monophosphate (cAMP) is poorly understood in the regulation of normal and abnormal hepatic cell growth. In this study, we examined the regulation of intracellular cAMP levels and its effect on nuclear cAMP responsive elements (CREs) in a rat model of hepatocellular carcinoma (HCC). Tumorigenic liver cells were cultured from an in vivo model of HCC and the role of cAMP in cell mitogenesis determined. These data demonstrated agents that elevate intracellular cAMP ([cAMP]i) levels caused significant dose-dependent inhibition of serum-stimulated mitogenesis in HCC cells. Cells were next analyzed for transcription factor expression and activity following increased [cAMP]i. These data demonstrated time- and dose-dependent increases in CRE binding protein (pCREB) activity, a maximal response occurring after 10-20 min before returning to basal levels within 60 min. In contrast, increased [cAMP]i levels led to sustained inducible cAMP early repressor (ICER) II/IIgamma mRNA and protein induction. To understand these data in relation to the in vivo setting, HCC tumors were analyzed and compared to pair-matched normal liver (NL) samples. These studies demonstrated significantly elevated Gsalpha-protein expression in HCC versus NL in the absence of significant changes in basal cAMP levels. Analysis of total and active CREB demonstrated significantly increased total CREB/pCREB in HCC versus NL. Further analysis of CRE expression demonstrated significantly increased expression of ICER mRNA and protein in HCC versus sham operated (Sh). These data demonstrate cAMP, while capable of stimulating promitogenic CREB activation inhibits cell mitogenesis in HCC possibly via ICER induction.
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PMID:Role of cyclic-AMP responsive element binding (CREB) proteins in cell proliferation in a rat model of hepatocellular carcinoma. 1611 Apr 70

HATs (histone acetyltransferases) contribute to the regulation of gene expression, and loss or dysregulation of these activities may link to tumorigenesis. Here, we demonstrate that expression levels of HATs, p300 and CBP [CREB (cAMP-response-element-binding protein)-binding protein] were decreased during chemical hepatocarcinogenesis, whereas expression of MOZ (monocytic leukaemia zinc-finger protein; MYST3)--a member of the MYST [MOZ, Ybf2/Sas3, Sas2 and TIP60 (Tat-interacting protein, 60 kDa)] acetyltransferase family--was induced. Although the MOZ gene frequently is rearranged in leukaemia, we were unable to detect MOZ rearrangement in livers with hyperplastic nodules. We examined the effect of MOZ on hepatocarcinogenic-specific gene expression. GSTP (glutathione S-transferase placental form) is a Phase II detoxification enzyme and a well-known tumour marker that is specifically elevated during hepatocarcinogenesis. GSTP gene activation is regulated mainly by the GPE1 (GSTP enhancer 1) enhancer element, which is recognized by the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2)-MafK heterodimer. We found that MOZ enhances GSTP promoter activity through GPE1 and acts as a co-activator of the Nrf2-MafK heterodimer. Further, exogenous MOZ induced GSTP expression in rat hepatoma H4IIE cells. These results suggest that during early hepatocarcinogenesis, aberrantly expressed MOZ may induce GSTP expression through the Nrf2-mediated pathway.
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PMID:Histone acetyltransferase MOZ acts as a co-activator of Nrf2-MafK and induces tumour marker gene expression during hepatocarcinogenesis. 1708 29

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

Several Ap1-like cis-acting elements were found within 5'-regulatory region (-2497...+173 versus transcription start point) of human apolipoprotein A-I gene (5'-apoA-I). Those elements are capable to interact with transcription factors belonging to Ap1 and CREB/ATF families. Those elements are localized outside of the hepatic enhancer (-220...-110) and the sequence responsible for apoA-I gene transcription in Caco2 cells (-595...-192). One of Ap1-like sites (5'-TGAGGTCT-3, Cre/jun2/apo) is present within 5'-apoA-I in two copies - distal (-1798 ...-1791) and proximal (+99...+106) ones. This and other Ap1-like sites - 5'-TGACTCT-3' (-1798...-1791, PF1) and 5'-TGACATCA-3' (-1171...-1163, Cre/jun1) were characterized by EMSA. It was shown by using the specific antibodies to c-Jun and ATF2 transcription factors in EMSA supershift experiments, that the DNA-protein complexes formed by Cre/jun2/apo, Cre/jun1 elements with nuclear proteins of human hepatoma HepG2 cells contain ATF2. The functional role of 5'-apoA-I regions containing Ap1-like sites was studied in cotransfection experiments of HepG2 cells (synthesize endogenous ApoA-I), human duodenum adenocarcinoma Hutu80 cells (do not synthesize endogenous ApoA-I), human neuroblastoma SK-N-SH cells (do not synthesize endogenous A-I) with expression vectors of c-jun and mekk1 genes. It was shown, that those Ap1-like sites appears to be responsible (the proximal Cre/jun2/apo is more efficient) for tissue-specific regulation of human apoA-I gene expression.
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PMID:[Ap1-like cis-elements in 5'-regulatory region of human apolipoprotein A-I gene]. 1861 Aug 38


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