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)

Independent of de novo protein synthesis, interleukin-1, interleukin-6, and dexamethasone caused immediate stimulation of transcriptional activity of most major acute phase plasma protein genes in the rat hepatoma H-35 cells. However, activation of alpha 2-macroglobulin and alpha 1-acid glycoprotein genes were delayed by 2-4 h and required ongoing protein synthesis. The hormones also increased transiently the transcription of the junB gene and the amounts of JunB, C/EBP, and C/EBP-like mRNA. To identify whether JunB and C/EBP have the ability to control both the early and late acute phase reactants, expression vectors for mouse C/EBP and JunB together with reporter gene constructs containing recognized hormone-specific regulatory elements were introduced into hepatoma cells. C/EBP displayed prominent transactivation activity with the interleukin-1 and glucocorticoid regulatory elements of alpha 1-acid glycoprotein, the interleukin-1 regulatory element of haptoglobin gene, and the interleukin-6 regulatory element of beta-fibrinogen. The interleukin-6 regulatory elements of the first two genes and the glucocorticoid response element of the third gene were not affected by C/EBP. These data suggest that normal hormone activation of these three acute phase reactant genes might involve, in part, C/EBP-related factors which have a broad range of specificity. H-35 cells stably transformed with a mouse C/EBP expression vector showed an elevated basal level as well as cytokine inducible expression of some but not all acute phase reactants. Cotransfected JunB resulted in reduced activity of cytokine-responsive constructs and in lower transactivation by C/EBP. JunB appears to function as a modulator of plasma protein expression during the course of acute phase response.
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PMID:Transcriptional regulation through cytokine and glucocorticoid response elements of rat acute phase plasma protein genes by C/EBP and JunB. 171 61

In an effort to identify protein factors that play a regulatory role in the differentiation of adipocytes, we have isolated two genes that encode polypeptides related to CCAAT/enhancer-binding protein (C/EBP; hereafter termed C/EBP alpha). The proteins encoded by these C/EBP-related genes, termed C/EBP beta and C/EBP delta, exhibit similar DNA-binding specificities and affinities compared with C/EBP alpha. Furthermore, C/EBP beta and C/EBP delta readily form heterodimers with one another as well as with C/EBP alpha. The transcriptional activating capacity of these two newly identified C/EBP isoforms was demonstrated by transient transfection experiments in which expression vectors encoding C/EBP beta and C/EBP delta were observed to induce transcription from the promoter of the serum albumin gene in cultured hepatoma cells. The mRNAs encoding C/EBP beta and C/EBP delta were detected in a number of tissues, most of which corresponded to sites of expression of C/EBP alpha. The expression pattern of C/EBP beta and C/EBP delta during adipose conversion of 3T3-L1 cells was examined by Western and Northern blotting assays. In contrast to the expression profile of the gene encoding C/EBP alpha, whose product is not detectable until the late phase of adipocyte differentiation, the c/ebp beta and c/ebp delta genes were actively expressed very early during adipocyte differentiation. Moreover, transcription of the c/ebp beta and c/ebp delta genes was observed to be induced directly by adipogenic hormones. The accumulation of C/EBP beta and C/EBP delta reached a maximal level during the first 2 days of differentiation and declined sharply before the onset of C/EBP alpha accumulation. The temporal pattern of expression of these three C/EBP isoforms during adipocyte differentiation may reflect the underpinnings of a regulatory cascade that controls the process of terminal cell differentiation.
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PMID:Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. 184 May 54

The gene (PP63) encoding the inhibitor (PP63) of the insulin receptor tyrosine kinase was isolated from a rat genomic library. The intron/exon organization was deduced from Southern-blot analysis and sequence data (i.e., the exons + the boundaries). The PP63 gene, which maps to chromosome 11, spans approx. 8 kb and contains seven exons separated by six introns of different sizes. All of the boundaries match the consensus GT/AG sequence for donor and acceptor splice sites. Primer extension and S1 mapping experiments were used to locate the transcription start point (tsp) 73 nt upstream from the translational initiator. Both in vitro transcription assays and transcription of a chimeric gene in intact hepatoma cells indicated that the sequence located immediately upstream from the tsp contained a promoter. Several putative cis-regulatory elements, including a TATA box and a C/EBP-binding site were found within the 250 bp preceding the tsp.
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PMID:Primary structure of the rat gene encoding an inhibitor of the insulin receptor tyrosine kinase. 184 62

We present a comparative study of the cis- and trans-acting elements governing the expression of the human transferrin (Tf) gene in two tissues, liver and testis, where Tf is expressed at various levels. We have previously identified the elements of the promoter, negative, and enhancer regions involved in the liver-specific expression of the gene. By transfection experiments of primary cultured rat Sertoli cells compared with hepatoma cells, DNase I footprinting, and gel retardation studies, we have analyzed 3.6 kilobase pairs of the Tf regulatory region. The far upstream enhancer functional in Hep3B cells is inactive in Sertoli cells; in the two cell types, different nuclear factors appear to bind to a DNA domain crucial for enhancer activity. Similar negative- and positive-acting elements are present in the distal promoter in both tissues. However different combinations of proximal promoter elements control tissue-specific expression. Liver-specific transcription is governed by the interaction of the Tf-LF1 protein and a C/EBP-related factor with the -125 to -45 region. In Sertoli cells, a -34 to -18 TATA box-binding factor is sufficient to initiate basal-level transcription. Efficient expression is achieved by the association of two factors binding either to the (-82, -1) or to the (-153, -52) region. The addition of a third adjacent element decreases the promoter activity, suggesting that the balance of three factors binding to the proximal sites regulates testis-specific expression.
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PMID:Sertoli cell-specific expression of the human transferrin gene. Comparison with the liver-specific expression. 185 57

The transthyretin (TTR) gene is regulated by two DNA regions which elicit hepatocyte-specific expression: a proximal promoter and distal enhancer. The TTR promoter and enhancer are composed of at least eight DNA binding sites for three different hepatocyte nuclear factors (HNF), CCAAT/enhancer binding protein (C/EBP), and AP-1/cJun. Site directed mutations within each of the HNF binding sites in the TTR promoter were introduced to evaluate their contribution to transcriptional activity in hepatoma cells. The data indicate that the strong affinity HNF-3-S binding site (-106 to -94) is absolutely required for TTR promoter activity since several mutations in this site eliminate TTR expression in the context of its enhancer. Conversion of a second weak affinity HNF3-W site (-140 to -131) in the TTR promoter to a high affinity site resulted in higher levels of expression. TTR mutations that disrupted several weak affinity sites (HNF1, HNF3-W, and HNF4) only slightly diminished expression levels in the presence of the TTR enhancer. In contrast, when we deleted the TTR enhancer from these HNF mutant constructs, TTR expression decreased to undetectable levels. This result suggests cooperation between the factors binding to the TTR promoter and enhancer regions. These results also demonstrate that the HNF3-S site alone is not sufficient to activate TTR transcription, but rather requires the participation of three cell-specific factors to elicit minimal promoter activity. The complexity of this promoter design and the requirement for a minimal number of cell-specific factors to achieve transcription allows us to propose a model which may explain the maintenance of tissue-specific expression of TTR.
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PMID:Site-directed mutagenesis of hepatocyte nuclear factor (HNF) binding sites in the mouse transthyretin (TTR) promoter reveal synergistic interactions with its enhancer region. 187 Sep 69

To investigate the regulation of genes whose expression is enriched in liver we studied expression of the albumin and transthyretin (TTR) genes in a series of rat hepatoma cell lines (FaO, C2, C2rev7, and H5) that express these genes at different rates. The level of expression of albumin and TTR was compared to the expression and DNA-binding activity of four transcription factors, HNF1/LFB1, C/EBP, HNF3, and HNF4, that are found at high concentrations in liver. We conclude that the levels of these factors are controlled both transcriptionally (HNF-3, HNF-4, and C/EBP) and post-transcriptionally (HNF-1/LFB1), and that the cellular concentration of these DNA-binding proteins helps explain the level of transcriptional activity observed for the genes they regulate.
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PMID:Differential regulation of hepatocyte-enriched transcription factors explains changes in albumin and transthyretin gene expression among hepatoma cells. 187 51

A cDNA clone encoding a thyroid-specific enhancer-binding protein (T/EBP) was isolated from a rat thyroid-derived FRTL-5 cell lambda gt 11 expression library, using a double-stranded oligonucleotide probe. This oligonucleotide was previously demonstrated to have the strongest binding affinity among three cis-acting DNA elements within the thyroid-specific enhancer region located 5.5 kbp upstream of the human thyroid peroxidase gene transcription start site. Nucleotide and deduced amino acid sequences of the cDNA revealed that T/EBP is identical to the previously reported thyroid-specific transcription factor 1 (TTF-1), which binds to the promoter of the rat thyroglobulin gene and controls its thyroid-specific expression. Expression of the T/EBP cDNA under control of the human cytomegalovirus major immediate-early gene promoter conferred thyroid-specific enhancer activity of as high as 26-fold to nonpermissive human hepatoma HepG2 cells when cotransfected with a vector containing 6.3 kbp of upstream sequence of the human thyroid peroxidase gene connected to a luciferase reporter gene. T/EBP was further expressed in HepG2 cells by using the vaccinia virus expression system. The expressed protein was partially purified by using sequence-specific affinity column chromatography and was further shown, by gel mobility shift experiments, to specifically bind to the enhancer-derived double-stranded oligonucleotide. These results clearly indicate that the binding of T/EBP (TTF-1) to the specific cis-acting enhancer element is largely responsible for thyroid-specific enhancer activity.
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PMID:Thyroid-specific enhancer-binding protein (T/EBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1. 192 26

The endogenous chicken vitellogenin II (VTGII) gene is transcribed exclusively in hepatocytes in response to estrogen. We previously identified two estrogen response elements (EREs) upstream of this gene. We now present an analysis of the VTGII promoter activated by these EREs in response to estrogen. Chimeric VTGII-CAT genes were cotransfected into LMH chicken hepatoma cells along with an estrogen receptor expression vector, and transient CAT expression was assayed after culturing the cells in the absence or presence of estrogen. An analysis of constructs bearing deletions downstream of the more proximal ERE indicated that promoter elements relevant to transcription in LMH cells extend to between -113 and -96. The relative importance of sequences within the VTGII promoter was examined by using 10 contiguous linker scanner mutations spanning the region from -117 to -24. Although most of these mutations compromised VTGII promoter function, one dramatically increased expression in LMH cells and also rendered the VTGII promoter capable of being activated by cis-linked EREs in fibroblasts cotransfected with an estrogen receptor expression vector. Gel retardation and DNase I footprinting assays revealed four factor-binding sites within this promoter. We demonstrate that three of these sites bind C/EBP, SP1, and USF (or related factors), respectively; the fourth site binds a factor that we denote TF-V beta. The biological relevance of these findings is suggested by the fact that three of these binding sites map to sites previously shown to be occupied in vivo in response to estrogen.
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PMID:Mutational studies reveal a complex set of positive and negative control elements within the chicken vitellogenin II promoter. 201 74

The transcription factor CCAAT/enhancer-binding protein (C/EBP) was found to selectively trans-activate one member of the human class I alcohol dehydrogenase (ADH) gene family. A comparison of the promoters for the three human class I ADH genes ADH1, ADH2, and ADH3 indicated a very similar pattern of binding sites (sites A-F) for rat liver nuclear proteins located between -10 and -210 base pairs (bp). In all three promoters site A consisted of two binding sites for the transcription factor C/EBP closely flanking both sides of the TATA box, but C/EBP bound with much greater affinity to site A of ADH2. C/EBP also bound at two locations which coincide with site D (-120 bp) and site E (-160 bp) of all three promoters. Cotransfection studies of human hepatoma cells using ADH-cat fusions and a C/EBP expression plasmid indicated that the human ADH2 promoter responded well to C/EBP trans-activation whereas the human ADH1 and ADH3 promoters, which bind C/EBP weakly, responded poorly. Individual mutations in several ADH2 nuclear factor-binding sites allowed the identification of four functional C/EBP-binding sites, i.e. two in site A as well as one each in sites D and E. Also, the ADH2 TATA box was found to be dispensable for C/EBP induction. Compared to ADH2 and ADH3, site A in ADH1 contains four extra base pairs between the two C/EBP motifs, and deletion of these nucleotides increased the C/EBP responsiveness of ADH1 presumably by changing the spacing of the two C/EBP motifs. Thus, sequence divergence of human class I ADH gene family members has led to forms which vary in their responsiveness to C/EBP. We suggest that C/EBP contributes to liver-specific expression of the human class I ADH gene family by selectively inducing the ADH2 gene via a TATA-independent mechanism during liver development.
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PMID:The role of CCAAT/enhancer-binding protein in the differential transcriptional regulation of a family of human liver alcohol dehydrogenase genes. 205 Jun 67

A promoter sequence between nucleotide -51 and nucleotide -10 in the human alcohol dehydrogenase gene ADH2 has been shown to bind the transcription factor CCAAT/enhancer-binding protein (C/EBP). A series of 5'-end deletions of the ADH2 promoter was cotransfected with a C/EBP expression plasmid in a human hepatoma cell line, and trans activation by C/EBP was seen when at least 171 base pairs of 5'-flanking DNA was present. Mutations in the ADH2 promoter indicate that the mechanism of C/EBP trans activation involves two binding sites, one located just upstream of the TATA box and one located in an unusual location between the TATA box and the transcription start point.
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PMID:trans activation of human alcohol dehydrogenase gene expression in hepatoma cells by C/EBP molecules bound in a novel arrangement just 5' and 3' to the TATA box. 216 45


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