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Query: UNIPROT:P06889 (Mol)
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The inducibility of metallothionein by cis- and trans-diamminedichloroplatinum(II) and their hydrolyzed products was studied in the JAr (a human choriocarcinoma) cell line. The metallothionein present in the cytosolic fraction of these cells was measured after a 12- or 24-h exposure to a fresh metal solution or a solution that had been allowed to hydrolyze. These results demonstrate that hydrolysis of the cis isomer produces a species that is able to give a 374% increase in the cytosolic level of metallothionein after a 24-h exposure to 40 microM of the metal. Fresh cisplatin, on the other hand, gives a maximal increase of 118% under the same conditions. Transplatin and its hydrolyzed species did not induce metallothionein. These results may indicate that hydrolysis of cisplatin performs an important role in the metabolism and possibly the toxicity of this widely used agent for cancer chemotherapy.
Mol Toxicol
PMID:Studies of induction of metallothionein in JAr (human choriocarcinoma) cells by cis and trans isomers of diamminedichloroplatinum (II) and their hydrolyzed species. 270 4

There is little information on the molecular events underlying the effects of cAMP on human chorionic gonadotropin (hCG) and particularly steroidal hormone production in normal trophoblasts. We examined the effects of 8-bromo-cAMP on mRNAs encoding two components of the cholesterol side-chain cleavage system, cytochrome P-450scc and adrenodoxin, and the alpha- and beta-subunits of hCG in cultured cytotrophoblasts. cAMP caused an increase in all of these mRNAs within 24 h, whereas actin mRNA declined. alpha-hCG mRNA increased first, followed by adrenodoxin, beta-hCG and cytochrome P-450scc mRNAs. The effects of 8-bromo-cAMP on alpha- and beta-hCG, adrenodoxin, and cytochrome P-450scc mRNAs, in cytotrophoblasts and JEG-3 choriocarcinoma cells, required the catalytic unit of protein kinases since H-7, a kinase inhibitor, blocked the increase in the mRNAs and prevented the stimulation of hCG and progesterone secretion. 8-Bromo-cAMP promoted a rapid increase in alpha-hCG mRNA in cytotrophoblasts in the presence of cycloheximide, an inhibitor of protein synthesis. In cytotrophoblasts, cycloheximide reduced basal and 8-bromo-cAMP-stimulated adrenodoxin mRNA abundance. In contrast, basal and cAMP-stimulated adrenodoxin mRNA was augmented by cycloheximide in JEG-3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1989 Jan
PMID:Effects of 8-bromo-cAMP on expression of endocrine functions by cultured human trophoblast cells. Regulation of specific mRNAs. 274 14

The alpha subunit of the placental hormone chorionic gonadotropin is regulated by cyclic AMP (cAMP) at the transcriptional level. A cAMP-responsive fusion gene (alpha-CAT) containing 1.5 kilobases of the alpha gene 5'-flanking sequence linked to the chloramphenicol acetyltransferase (CAT) gene was used as a transcriptional reporter in competition assays in transfected JEG-3 choriocarcinoma cells. Expression of the alpha-CAT fusion gene increased linearly with increasing amounts of transfected plasmid and was maximal at the same amount of alpha-CAT DNA (2 micrograms) with or without cAMP treatment. Various amounts of different competitor DNA sequences were cotransfected with the alpha-CAT reporter plasmid to examine the interactions of intracellular trans-acting factors with the regulatory elements of the alpha gene promoter. An 800-base-pair fragment of alpha gene 5'-flanking sequence inhibited both basal and cAMP-stimulated transcription of the alpha-CAT reporter plasmid in a dose-dependent manner, indicative of interactions with one or more trans-acting factors that activate alpha gene expression. The alpha gene sequences that interact with intracellular regulatory factors were defined by using several discrete regions of the 5'-flanking sequence as competitors for alpha-CAT expression. A proximal promoter sequence (-99 to +44) containing the CCAAT box, TATA box, and transcriptional initiation site was a relatively ineffective competitor of alpha-CAT transcription. In contrast, an upstream sequence between -236 and -100 was an effective competitor for transcriptional activators of alpha-CAT expression. Competition for alpha-CAT expression by this regulatory sequence did not require cis interactions with downstream promoter elements and was equally effective with or without cAMP treatment. An 18-base-pair repeated sequence within this region of the alpha gene (-146 to -111) greatly enhanced both basal gene expression and cAMP responsivity and also competed for limiting cellular transcription factors. These findings suggest that JEG-3 cells contain trans-acting factors that interact with a cAMP response element to activate alpha gene transcription. The chorionic gonadotropin beta gene 5'-flanking sequence also competed for alpha-CAT expression, suggesting that a common trans-acting factor is shared by the regulatory sequences of the alpha and beta genes.
Mol Cell Biol 1987 Sep
PMID:trans-acting factors interact with a cyclic AMP response element to modulate expression of the human gonadotropin alpha gene. 282 16

The McDonough strain of feline sarcoma virus contains an oncogene called v-fms whose ultimate protein product (gp140v-fms) resembles a cell surface growth factor receptor. To identify and characterize the protein product of the proto-oncogene c-fms, antisera were prepared to the viral fms sequences and used to detect specific cross-reacting sequences in human choriocarcinoma cells (BeWo) known to express c-fms mRNA. Both tumor-bearing rat sera and a rabbit antiserum prepared to a segment of v-fms expressed in Escherichia coli detected a 140-kilodalton (kDa) glycoprotein in the BeWo cells. Tryptic fingerprint analysis of [35S]methionine-labeled proteins indicated that the viral fms proteins and the 140-kDa BeWo cell protein were highly related. This 140-kDa glycoprotein contained an associated tyrosine kinase activity in vitro and was labeled principally on serine after 32Pi metabolic labeling. These results suggest that the 140-kDa protein in BeWo cells is the protein product of the human c-fms proto-oncogene. This conclusion is supported by the finding that a similar protein is detectable only in other human cells that express c-fms mRNA. These other human cells include adherent monocytes and the cell line ML-1, which can be induced to differentiate along the monocyte-macrophage pathway. This is in agreement with current thought that the c-fms proto-oncogene product functions as the CSF-1 receptor specific to this pathway.
Mol Cell Biol 1985 Dec
PMID:Characterization of the human c-fms gene product and its expression in cells of the monocyte-macrophage lineage. 301 21

The effects of cholera toxin (CT), which stimulates adenylate cyclase, 12-O-tetradecanoylphorbol 13-acetate (TPA), a protein kinase C activator, epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on progesterone (P) and estradiol (E2) secretion by human choriocarcinoma JEG-3 cells were studied. During a 48 h incubation, CT, TPA and EGF stimulated P production in a concentration-dependent manner, whereas IGF-I was without effect. CT (1.0 ng/ml), TPA (10 ng/ml) and EGF (10 ng/ml) stimulated P production maximally 4.3-, 3.3- and 2.3-fold over basal, respectively. When added together with CT, TPA and EGF stimulated P production 10.0- and 5.0-fold over basal production showing that the effects of CT plus TPA were more than additive but those of CT plus EGF less than additive. Time-course studies indicated that the effects were detectable at 12 h, and continued to increase up to 48 h. The conversion of added dehydroepiandrosterone sulfate (DHEAS) to E2 was stimulated by CT and TPA and inhibited by IGF-I in a concentration-dependent manner. By contrast, EGF had no effect. The maximal responses in E2 production were 3.2- and 2.0-fold over unstimulated cells by CT (1.0 ng/ml) and TPA (10 ng/ml), respectively. When both agents were added together, their effects on E2 production were additive with 5.5-fold increase over unstimulated cells. IGF-I (30 ng/ml) inhibited maximally basal and CT-stimulated E2 production by 33% and 42%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1988 Sep
PMID:Modulation of steroidogenesis in choriocarcinoma cells by cholera toxin, phorbol ester, epidermal growth factor and insulin-like growth factor I. 326 54

In addition to its synthesis in the developing placenta, human CG or the isolated alpha- and beta-subunits are synthesized by a wide variety of both trophoblastic and nontrophoblastic tumor cell lines. The beta-subunit confers unique biological activity on the hormone and is encoded by a family of six genes or pseudogenes linked physically with beta LH at one locus on chromosome 19. Previous work has demonstrated that members of the beta CG family are not expressed to the same extent in first-trimester placenta. The factors allowing differential expression of the six nearly identical genes are unknown. It is also undetermined which of the multiple beta CG genes are actively expressed in the tumor cell lines that produce beta-subunit ectopically. One potential mechanism for control of beta CG gene expression is DNA methylation. A unique method of two-dimensional DNA electrophoresis was used to analyze the methylation status of each of the individual beta CG genes in placenta and in tumor cell lines that either do or do not express the protein. The DNA from each source exhibited unique, reproducible methylation patterns over the six beta CG genes. Particularly interesting were the observations that: 1) despite their nearly identical sequences and close chromosomal proximity, the six beta CG genes are distinguished from one another within the same and different cell types by their extent and pattern of methylation; 2) the beta CG locus is significantly hypomethylated in placenta, a state maintained in choriocarcinoma cells (JAr); 3) the beta CG gene cluster is unmethylated at a limited set of sites in DNA from both 2RA (a transformed fibroblast cell line that does not produce beta-subunit) and CBT (a glioblastoma cell line that produces beta-subunit ectopically), suggesting that general demethylation of the domain does not accompany activation of the locus in CBT but rather that site-specific changes may be responsible, at least in part, for inappropriate beta CG expression; and 4) the ratio of beta CG gene 3 transcripts to beta CG gene 5 transcripts is at least 10-fold higher in CBT cells than in JAr cells, suggesting that the reduced methylation in CBT cells of gene 3 compared to gene 5 may be a factor contributing to the activity of these genes.
Mol Endocrinol 1993 Oct
PMID:Differential DNA methylation of the chorionic gonadotropin beta-subunit multigene family. 750 95

The human glycoprotein hormone alpha-gene is transcriptionally activated by cAMP in placental cells. We have shown that the novel hypothalamic peptide, pituitary adenylate cyclase activating polypeptide, PACAP-38, significantly stimulates intracellular cAMP levels (12-fold increase; P < 0.001) in JEG-3 choriocarcinoma cells. Regulation of alpha-promoter activity was assessed using both the chloramphenicol acetyl transferase (CAT) and the luciferase (LUC) reporter gene systems. alpha-CAT activity was significantly stimulated by PACAP-38 (4-fold increase; P < 0.05) at 24 h with a similar stimulation being seen with a LUC expression vector. The kinetics of stimulation of the alpha-promoter by PACAP-38 were similar to those seen with 8-Br-cAMP and vasoactive intestinal polypeptide (VIP), a peptide which shares 68% homology with PACAP-38. PACAP-38 also stimulated the production of IL-6 from JEG-3 cells with a time course of response similar to that of alpha-promoter transcription. We conclude that human placental choriocarcinoma cells possess functional receptors for PACAP-38, whose activation enhances cAMP formation, alpha-subunit gene transcription and interleukin-6 (IL-6) production.
Mol Cell Endocrinol 1994 Feb
PMID:PACAP-38 positively regulates glycoprotein hormone alpha-gene expression in placental cells. 751 49

The biosynthesis of human chorionic gonadotrophin (hCG) is a hallmark endocrine function of human choriocarcinoma cells. The present study investigated the consequences of greatly diminishing this synthesis in JAR cells by stably transfecting them with pRSV-antisense hCG-alpha cDNA expression vector. The vector directs the synthesis of antisense hCG-alpha subunit mRNA which would then bind to sense hCG-alpha subunit mRNA, thus blocking its translation and consequently dimer hCG protein synthesis. The transfection with pRSV-antisense hCG-alpha cDNA resulted in a dramatic decrease in hCG secretion as compared with untransfected parental cells or those transfected with an empty vector used for the selection of clones. The decreased secretion was due to a decreased synthesis which in turn was due to a fall in steady-state hCG-alpha and -beta subunit mRNA levels. The decrease of hCG-beta subunit transcripts was unexpected and it was not due to contamination of antisense hCG-alpha cDNA construct with hCG-beta sequence. The transcription of hCG-alpha and -beta subunit genes was not altered in transfected cells suggesting that increased degradation was responsible for decreased steady-state hCG subunit mRNA levels. Despite the decreased hCG levels, the transfected cells maintained normal hCG receptor levels, responded to epidermal growth factor stimulation of hCG synthesis and secretion and grew at the same rate as the control parental cells and those transfected with an empty vector.
J Mol Endocrinol 1995 Jun
PMID:Consequences of antisense human chorionic gonadotrophin-alpha subunit cDNA expression in human choriocarcinoma JAR cells. 754 1

Three regions of the human placental lactogen (hPL) promoter that contain several half-site motifs that closely resemble the responsive elements for thyroid hormone (TR), all trans retinoic acid (RAR) and 1,25 dihydroxyvitamin D3 (VDR) have been identified and characterized. Transfection studies in BeWo choriocarcinoma cells indicate that site A (nt -979 to -954) is responsive to RAR alpha but not TR beta. Site B (nt -1140 to -1170) is responsive to both RAR alpha and TR beta, and site C (nt -550 to -580) is not responsive to either RAR alpha or TR. These findings, together with the observation that placental cells express retinoid receptors and TRs, strongly suggest a role for these receptors in the regulation of the hPL gene. Site B on the hPL promoter is able to integrate the responses to RA and T3 through a single element.
Mol Cell Endocrinol 1995 Jul
PMID:Identification of a composite steroid hormone response element on the human placental lactogen promoter. 758 79

The human aromatase cytochrome P450 gene, CYP 19, spans more than 75 kb in the human genome. Recently, it is proposed that the expression of the CYP 19 gene is regulated in part by tissue-specific promoters through the use of mechanisms involving alternative splicing of a number of untranslated exons. In this study, we have characterized cis-acting elements involved in the transcriptional regulation of the gene in human placental cells, where the majority of the transcripts contain the 5'-untranslated sequence encoded by exon I.1. By transient expression analyses in human BeWo choriocarcinoma cells using the bacterial chloramphenicol acetyltransferase gene as a reporter gene, we localized an enhancer element in the region between -242 and -166 relative to the major cap site of the gene. Furthermore, we demonstrate that the element between -2141 and -2115 participates in the 12-O-tetradecanoylphorbol 13-acetate (TPA)-mediated enhancement of gene expression. By screening a human placental cDNA expression library, we have isolated a cDNA clone (lambda 1-2) encoding a peptide which binds specifically to the element between -2141 and -2115. Sequence analysis of the clone revealed that the insert of lambda 1-2 encodes a part of the amino acid sequence of NF-IL6 (also termed as LAP and C/EBP beta). Northern blot analysis reveals expression of the NF-IL6 gene in BeWo cells and human placenta. These results indicate that NF-IL6 is one of the nuclear factors which participate in TPA-mediated transcriptional enhancement of CYP 19 gene expression.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Transcriptional regulation of the human aromatase cytochrome P450 gene expression in human placental cells. 762 51


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