Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modulation of DNA synthesis by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied in primary cultures of hepatocytes and in rat liver epithelial cells (WB-F344) to develop models for studies on the interactions between the activated Ah receptor and cellular growth control. In hepatocytes TCDD either positively or negatively modulated EGF-stimulated DNA synthesis. In the presence of ethinylestradiol 10(-12) M TCDD moderately increased EGF-stimulated DNA synthesis (approximately 30%). In contrast, 10(-9) M TCDD in the absence of ethinylestradiol decreased DNA synthesis (approximately 30%). Analysis of variance revealed that the TCDD effects were highly significant. The response of 'early genes' of the jun/fos family and the corresponding proteins was also studied under these two conditions. In agreement with the DNA synthesis data, the level of c-Jun was increased or decreased in nuclear extracts. Furthermore, DNA binding of Jun/Fos proteins, including c-Jun and Fra-1, was decreased under conditions of mitoinhibition, while the level of Fra-1 in nuclear extracts was increased. In WB-F344 cells TCDD treatment for 44 h increased DNA synthesis 2- to 3-fold in comparison with controls, based on measuring [3H]thymidine incorporation into DNA or on determining the nuclear labeling index with bromodeoxyuridine. This effect is probably due to inhibition of high density growth arrest by TCDD. The proposed cellular models may be useful to elucidate the interactions between the activated Ah receptor and signaling pathways of growth homeostasis.
Carcinogenesis 1996 Feb
PMID:Growth modulation of hepatocytes and rat liver epithelial cells (WB-F344) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 862 38

We studied the effects of bile acids on inducibility of the transcription factor AP-1 in human colon carcinoma LoVo cells. Firstly, cells were treated with chenodeoxycholic acid and the nuclear extracts from those cells were processed by electrophoretic mobility shift assays to analyze nuclear AP-1 DNA-binding activity. We demonstrated that chenodeoxycholic acid induced AP-1 DNA-binding activity in a dose- and time-dependent fashion. Antibody supershift experiments clearly revealed that the majority of protein components in induced AP-1 DNA-binding activity were the products of oncogenes c-fos and c-jun. On the other hand, DNA-binding activity in the nuclear extracts for either NF kappa B, Sp1, or ATF/CREB was not affected by bile acids, suggesting that the effect of bile acids was rather specific for AP-1. Transient transfection experiments supported this notion: expression of the AP-1-luciferase reporter construct was induced by bile acids in a dose-dependent manner, and expression of either reporter construct for NF kappa B, Sp1, or ATF/CREB was not influenced by treatment of the cells with bile acids. We also demonstrated that those bile acids efficiently activated AP-1-dependent promoter in DLD-1 cells, which (as well as LoVo cells), are derived from colon adenocarcinoma, but not in COLO320DM cells which are from colon carcinoid tumor. Thus, we may indicate that bile acids exclusively induce nuclear AP-1 activity in colon adenocarcinoma cells.
Carcinogenesis 1996 Mar
PMID:Induction of the transcription factor AP-1 in cultured human colon adenocarcinoma cells following exposure to bile acids. 863 Nov 27

Benzo[a]pyrene 7,8-dihydrodiol 9,10-epoxide is an established carcinogen, known to covalently bind to DNA, in particular to the exocyclic aminogroup of dG, and thereby cause conformational changes to the double helix. AP-1 is a well-studied transcription factor that specifically binds to the DNA sequence 5'-d(TGAGTCA). The effects of more or less randomly distributed BPDE adducts on DNA have been studied in different contexts, as well as the effects of different stimuli on transcription factor binding affinity and expression, but so far no investigation has been made concerning the effect of specific modification of a transcription factor binding site. In this study we have specifically modified the binding site of the transcription factor AP-1 with the (+)-anti- or (-)-syn-enantiomers of BPDE, and have studied how this affects the binding of the Fos-Jun proteins. Both (-)-syn- and (+)-anti-BPDE, giving rise to a cis- and a trans-adduct, respectively, have been used and, in both cases, the binding of AP-1 like proteins from HeLa cell nuclear extracts to the modified binding site decreased by approximately 50% as compared to controls. There was no apparent difference in response between the different diastereomers, so it seems that the binding geometry of the adduct (either intercalated or pointing towards the 5'-end in the minor groove, respectively) is of less importance. An interesting feature was the apparent yield of three differently shifted bands using the modified binding site. This can be due to conformational changes of the complex and/or the presence of less specific complexes as an effect of the adduct. Recombinant, truncated Fos-Jun proteins completely failed to bind to modified binding sites when performing the same experiments as detailed above and their binding to unmodified oligonucleotide was 50% less than for native proteins from the nuclear extract. Supershift assays, using antibodies specific for c-Fos and c-Jun proteins, and competition experiments with various unlabelled oligonucleotides, were performed in order to check the specificity of binding in the observed bands. The results using the oligonucleotide containing the unmodified binding sequence and HeLa cell nuclear extract were fully consistent with binding of c-Fos and c-Jun, whereas the binding to oligonucleotides containing BPDE-modified binding sequences was not. This implies involvement of other proteins in this event.
Carcinogenesis 1996 Sep
PMID:Inhibitory effects on the DNA binding of AP-1 transcription factor to an AP-1 binding site modified by benzo[a]pyrene 7,8-dihydrodiol 9,10-epoxide diastereomers. 882 21

Rat glutathione transferase P (GST-P) is expressed at low levels in the normal liver but becomes highly expressed in hyperplastic nodules and in hepatocellular carcinomas during chemical hepatocarcinogenesis. To understand the regulation mechanisms of this gene, we have characterized the 5'-flanking region and have found that GST-P gene is regulated by at least two elements: one is a strong enhancer and the other is a silencer. GST-P enhancer I (GPEI), located at -2.5 Kb, consists of two TPA-responsive element (TRE)-like sequences that are palindromically oriented with 3 bp in between. It is well known that TRE is activated by two nuclear oncogenes, c-Jun and c-Fos. Although GPEI is trans-activated by these oncogenes, it is also active in F9 embryonal carcinoma cells that lack c-Jun protein, suggesting that it can function with some trans-activator other than AP-1 (c-Jun/c-Fos heterodimer). Indeed, another protein is identified from the F9 nuclear extract. We have also identified a silencer element at 300 bp upstream from the cap site. There are several cis-elements in this region and at least three trans-acting factors bind to these elements. We purified SF-A (silencer factor A) which binds to several regions in this silencer, and determined the partial amino acid sequence. Interestingly, SF-A seemed to be a related protein to NF1 (nuclear factor 1) which is an activator for the transcription and DNA replication. Another factor SF-B (silencer factor B) has been cloned and found to be the same as LIP (liver inhibitory protein) which is a competitor for LAP (liver activator protein), both are from the same gene designated as C/EBP beta. By transfection analysis using GAL4 DNA binding domain we found LIP is not only a competitor but a direct repressor. In the normal liver, another C/EBP family member, C/EBP alpha also acts as a negative regulator, and this expression decreases during hepatocarcinogenesis, resulting in the loss of silencer function. We carried out the carcinogenesis experiments using transgenic rats harboring a chloramphenicol acetyltransferase (CAT) reporter gene with -2900 to + 59 of the GST-P gene. Liver foci and nodules produced by chemical carcinogens were found to express high levels CAT activity by both CAT assay and immunohistochemical study, while normal liver cells did not express any CAT activity. These results demonstrate that the GST-P gene is trans-activated locus-independently during rat hepatocarcinogenesis. Moreover, the similar results were obtained using transgenic rats carrying GPEI-CAT, indicating that GPEI is an important cis-element for activation of GST-P gene during hepatocarcinogenesis.
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PMID:[Regulation mechanism of specific expression of tumor marker gene during carcinogenesis]. 883 Dec 56

Manganese superoxide dismutase (MnSOD) has been found to be depleted in a variety of tumor cells as well as in in vitro transformed cell lines, suggesting that MnSOD may function as an anticarcinogen by protecting the cell from oxidant-induced carcinogenesis. The relationship between MnSOD expression and tumor promotion was studied by transfection of a human MnSOD cDNA into the promotable mouse epidermal cell line JB6 clone41. The effect of MnSOD overexpression on the promotion-sensitive phenotype of JB6 cells was assessed by measuring growth characteristics such as growth rate and the ability to form colonies in soft agar. Compared with the parental and vector-transfected (gpt) control cells, MnSOD-overexpressing cells had a slower growth rate and their ability to form colonies in soft agar was significantly decreased in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. Since the transformation-sensitive phenotype of JB6 clone41 cells is associated with increased expression of the transcription factor AP-1, we compared c-jun and c-fos mRNA expression in MnSOD-transfected and control JB6 cells. Overexpression of MnSOD led to a significant decrease in c-jun and c-fos expression in response to treatment with TPA or the oxidant promoter superoxide. These findings indicate that the promotion-sensitive phenotype of JB6 clone41 cells can be reverted by increasing MnSOD intracellularly. A possible mechanism is that elevated MnSOD expression might change the intracellular redox state by altering the balance of reactive oxygen species. This could lead to a modulation of TPA and oxidant-induced signal transduction pathways controlling cell growth and differentiation.
Carcinogenesis 1997 Mar
PMID:Manganese superoxide dismutase expression inhibits soft agar growth in JB6 clone41 mouse epidermal cells. 906 45

To determine whether normal breast cells have different levels of activating protein 1 (AP-1) expression and activation relative to breast cancer cells, we have compared the level of c-Jun and c-Fos expression and AP-1 activity in human mammary epithelial cells (HMECs) at different stages of transformation (normal proliferating HMECs, immortal HMECs, oncogene-transformed HMECs, and breast cancer cell lines). These studies demonstrated that normal and immortal HMECs have a high basal level of expression of cJun and cFos and higher AP-1 DNA-binding and transcriptional activating activities than do oncogene-transformed HMECs or human breast cancer cells, with a gradual decrease in AP-1 transactivating activity as cells progress through the carcinogenesis pathway (normal > immortal > oncogene-transformed > cancer cell lines). The AP-1 activity in normal or immortal cells was not modulated by growth factor supplementation or oncogene overexpression, as it is in breast cancer cells. However, the addition of suramin, a nonspecific growth factor antagonist, did inhibit AP-1 in these HMECs, suggesting that this high level of AP-1 present in normal HMECs may be due to autocrine stimulation of growth factor pathways. The differences in AP-1 activity in normal and malignant breast cells may indicate that normal cells are more dependent on AP-1-mediated signals for their growth than are breast cancer cells.
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PMID:Breast cancer cells have lower activating protein 1 transcription factor activity than normal mammary epithelial cells. 923 Feb 21

(-)-Epigallocatechin gallate (EGCG) and theaflavins are believed to be key active components in tea for the chemoprevention against cancer. However, the molecular mechanisms by which EGCG and theaflavins block carcinogenesis are not clear. We have used the JB6 mouse epidermal cell line, a system that has been used extensively as an in vitro model for tumor promotion studies, to examine the anti-tumor promotion effects of EGCG and theaflavins at the molecular level. EGCG and theaflavins inhibited epidermal growth factor- or 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation in a dose-dependent manner. At the dose range (5-20 microM) that inhibited cell transformation, EGCG and theaflavins also inhibited AP-1-dependent transcriptional activity and DNA binding activity. The inhibition of AP-1 activation occurs through the inhibition of a c-Jun NH2-terminal kinase-dependent, but not an extracellular signal-regulated protein kinase (Erk) 1-dependent or Erk2-dependent, pathway. Because the transcription factor AP-1 is important for tumor promoter-induced neoplastic transformation, the inhibitory effects on AP-1 activation by EGCG and theaflavins may further explain the anti-tumor promotion action of these tea constituents.
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PMID:Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols, (-)-epigallocatechin gallate, and theaflavins. 933 Nov 5

Curcumin (diferuloylmethane), the naturally occurring yellow pigment in turmeric and curry, is isolated from the rhizomes of the plant Curcuma longa Linn. Curcumin inhibits tumorigenesis during both initiation and promotion (post-initiation) periods in several experimental animal models. Topical application of curcumin inhibits benzo[a]pyrene (B[a]P)-mediated formation of DNA-B[a]P adducts in the epidermis. It also reduces 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in skin inflammation, epidermal DNA synthesis, ornithine decarboxylase (ODC) mRNA level, ODC activity, hyperplasia, formation of c-Fos, and c-Jun proteins, hydrogen peroxide, and the oxidized DNA base 5-hydroxymethyl-2'-deoxyuridine (HmdU). Topical application of curcumin inhibits TPA-induced increases in the percent of epidermal cells in synthetic (S) phase of the cell cycle. Curcumin is a strong inhibitor of arachidonic acid-induced edema of mouse ears in vivo and epidermal cyclooxygenase and lipoxygenase activities in vitro. Commercial curcumin isolated from the rhizome of the plant Curcuma longa Linn contains 3 major curcuminoids (approximately 77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin). Commercial curcumin, pure curcumin, and demethoxycurcumin are about equipotent as inhibitors of TPA-induced tumor promotion in mouse skin, whereas bisdemethoxycurcumin is somewhat less active. Topical application of curcumin inhibits tumor initiation by B[a]P and tumor promotion by TPA in mouse skin. Dietary curcumin (commercial grade) inhibits B[a]P-induced forestomach carcinogenesis, N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)-induced duodenal carcinogenesis, and azoxymethane (AOM)-induced colon carcinogenesis. Dietary curcumin had little or no effect on 4-(methylnitosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis and 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast carcinogenesis in mice. Poor circulating bioavailability of curcumin may account for the lack of lung and breast carcinogenesis inhibition.
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PMID:Inhibitory effects of curcumin on tumorigenesis in mice. 959 Nov 90

Exposure of mammalian cells to UV irradiation stimulates phosphatidylcholine hydrolysis and activates the transcription factor AP-1. Since phosphocholine (PCho), a phospholipid metabolite, is a potential regulator of mitogenesis and carcinogenesis, we examined the effect of UV exposure on the formation of PCho and the possible mediatory role of PCho in UVB-and UVC-induced activation of AP-1 in mouse JB6 epidermal cells. We found that both UVB and UVC irradiation resulted in increased PCho levels. Hemicholinium-3 (HC-3), an inhibitor of choline kinase, strongly inhibited UV-induced AP-1 activity. By contrast, relatively low levels of PCho (80 microM) or choline (20 microM) nearly doubled UV-induced AP-1 activity, while higher (2-20 mM) concentrations of PCho alone stimulated AP-1 activity 6-8-fold. Importantly, HC-3 inhibited only the stimulatory effect of choline, but not of PCho, on AP-1 activity. Of the mitogen-activated protein (MAP) kinases involved in the regulation of AP-1 activity, UVC stimulated the MAP kinase family ERK-1/ERK-2, JNK as well as p38 kinase activity. These UVC effects were all inhibited by HC-3. With UVB, by contrast, only the activation of ERK-1/ERK-2 was inhibited by HC-3. The data suggest that increased formation of PCho is required for UV-induced activation of AP-1 by an ERK-1/ERK-2-dependent mechanism.
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PMID:Increased synthesis of phosphocholine is required for UV-induced AP-1 activation. 977 51

Calpain, also named CANP (for calcium-activated neutral protease), is an intracellular cytoplasmatic non-lysosomal cysteine endopeptidase that requires calcium ions for activity. Many substrates of the calpain isoenzymes, such as the transcription factors c-Fos and c-Jun, the tumor supressor protein p53, protein kinase C, pp60c-src and the adhesion molecule integrin, have been implicated in the pathogenesis of different human tumors, suggesting an important role of the calpains in malignant diseases. We now report differential expression of the calpain I gene (CL I) in a variety of tumors, extending our study to a larger series of renal cell carcinomas. Using Northern-blot analysis, we studied calpain I expression in 30 renal cell carcinomas as compared with matched healthy tissues. Tumor samples were classified according to their histological type: 21 clear cell carcinomas, 4 chromophobe carcinomas, 3 papillary carcinomas and 2 oncocytomas. In renal tumor samples, calpain I gene mRNA was expressed at highly variable levels, significantly depending on the different histological types. Moreover, there was a correlation of higher calpain I expression with increased malignancy: within the clear cell carcinoma subset, tumor samples with advanced nodal status (N1 and N2) showed a significantly higher calpain I expression than tumors without metastasis to regional lymph nodes. Our data suggest an important role of calpain isoenzymes in carcinogenesis and tumor progression.
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PMID:Expression of calpain I messenger RNA in human renal cell carcinoma: correlation with lymph node metastasis and histological type. 998 24


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