Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we showed that when a DNA fragment extending from -3067 to -2734 of the human apolipoprotein B (apo-B) gene is inserted immediately upstream of an apo-B promoter segment (-139 to +121), transcription from this promoter is reduced by about 10-fold in cultured colon carcinoma cells (CaCo-2) but not in cultured hepatoma cells (HepG2). We postulated that this reducer operates by a mechanism involving active repression of a transcriptional activator that binds to the segment from -111 to -88 of the apo-B promoter (B. Paulweber and B. Levy-Wilson, J. Biol. Chem. 266:24161-24168 1991). In the current study, the reducer element has been localized to a 24-bp sequence from -2801 to -2778 of the apo-B gene that contains a binding site for the negative regulatory protein ARP-1. Furthermore, we have demonstrated that the transcription factor hepatocyte nuclear factor 3 alpha (HNF-3 alpha) binds to the sequence 5'-TGTTTGCTTTTC-3' from -95 to -106 of the apo-B promoter, to stimulate transcription. Transcriptional activation by HNF-3 is repressed when the reducer sequence is inserted immediately upstream of the HNF-3 binding site, suggesting a mechanism by which the reducer-bound protein blocks the activation promoted by HNF-3. Data from cotransfection experiments in which ARP-1 is overexpressed in the absence of its binding site suggest that ARP-1 interacts either directly or via a mediator protein with proteins recognizing the HNF-3 site and that this interaction is sufficient to repress transcriptional activation by HNF-3. Because transcriptional activation by Sp1 is not affected by the reducer, it is unlikely that the reducer interacts directly with basic components of the transcriptional machinery.
 ...
PMID:The mechanism by which the human apolipoprotein B gene reducer operates involves blocking of transcriptional activation by hepatocyte nuclear factor 3. 844 95

The p53 tumor suppressor gene is a transcriptional activator involved in cell cycle regulation, apoptosis, and DNA repair. We have shown that p53 is required for efficient nucleotide excision repair of UV-induced DNA photoproducts from global genomic DNA but has no effect on transcription-coupled repair. In order to evaluate whether p53 influences repair indirectly through cell cycle arrest following DNA damage or plays a direct role, we examined repair in vivo in human cells genetically altered to disrupt or regulate the function of p53 and p21. Both primary human fibroblasts and HCT116 colon carcinoma cells wild type for p53 but in which the p21 gene was inactivated through targeted homologous recombination showed no decrease in global repair of UV photoproducts. Human bladder carcinoma cells mutant for p53 and containing a tetracycline-regulated p21 cDNA showed no significant enhancement of repair upon induction of p21 expression. All of the cell lines, including the mismatch repair-deficient, MLH1 mutant HCT116 cells, were proficient for transcription-coupled repair. Clonogenic survival of HCT116 cells following UV irradiation showed no dependence on p21. Therefore, our results indicate that p53-dependent nucleotide excision repair does not require the function of the p21 gene product and is independent of p53-regulated cell cycle checkpoints.
 ...
PMID:The p53-regulated cyclin-dependent kinase inhibitor, p21 (cip1, waf1, sdi1), is not required for global genomic and transcription-coupled nucleotide excision repair of UV-induced DNA photoproducts. 1133 Dec 89

Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. To gain insight into ES-mediated signaling, we studied the effects of ES RNA on Xenopus embryogenesis and observed developmental abnormalities consistent with impaired Wnt signaling. ES RNA blocked the axis duplication induced by beta-catenin, partially suppressed Wnt-dependent transcription, and stimulated degradation of both wild-type and "stabilized" forms of beta-catenin, the latter suggesting that ES signaling does not involve glycogen synthase kinase 3. Moreover, ES uses a pathway independent of the Siah1 protein in targeting beta-catenin for proteasome-mediated degradation. ES failed to suppress the effects of T cell-specific factor (TCF)-VP16 (TVP), a constitutive downstream transcriptional activator that acts independently of beta-catenin. Importantly, these data were replicated in endothelial cells and also in the DLD-1 colon carcinoma cells with the mutated adenomatous polyposis coli protein. Finally, suppression of endothelial cell migration and inhibition of cell cycle by ES were reversed by TVP. Though high levels of ES were used in both the Xenopus and endothelial cell studies and the effects on beta-catenin signaling were modest, these data argue that at pharmacological concentrations ES may impinge on Wnt signaling and promote beta-catenin degradation.
 ...
PMID:Endostatin is a potential inhibitor of Wnt signaling. 1214 76

Mirk/dyrk1B is an arginine-directed protein kinase, which functions as a transcriptional activator and mediates serum-free growth of colon carcinoma cells by an unknown mechanism. We now report that turnover of the cdk inhibitor p27(kip1) and the G(1)-phase cyclin cyclin D1 is enhanced in each of 4 Mirk stable transfectants compared to vector control transfectants and Mirk kinase-inactive mutant transfectants. This enhanced turnover is proteasome-dependent and leads to lower protein levels of both p27(kip1) and cyclin D1. Lower protein levels of the cdk inhibitor p21(cip1) were also observed in the 4 Mirk stable transfectants. Mirk did not alter the activity of a p27(kip1) promoter construct or p27(kip1) mRNA levels by stable expression, indicating that the decrease in p27(kip1) protein levels was due to a posttranscriptional mechanism. These data are consistent with mirk enhancing the expression of some component common to the proteolysis of both p27(kip1) and cyclin D1.
 ...
PMID:Rapid turnover of cell-cycle regulators found in Mirk/dyrk1B transfectants. 1245 49

Prostaglandin E(2) (PGE(2)) has been implicated as an inducer of angiogenesis in human colon cancer. Here, we demonstrate that PGE(2) exposure induces the expression of vascular endothelial growth factor (VEGF) mRNA in HCT116 human colon carcinoma cells that is mediated by the transcriptional activator hypoxia-inducible factor 1 (HIF-1). PGE(2) exposure induces the phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Pharmacologic inhibition of ERK phosphorylation blocks the induction of VEGF mRNA and HIF-1alpha protein expression in response to PGE(2) stimulation. Inhibition of C-SRC tyrosine kinase activity also blocks PGE(2)-induced HIF-1alpha protein and VEGF mRNA expression without blocking ERK phosphorylation. In contrast, phosphorylation of AKT is dependent on ERK and C-SRC activity. Thus, the activity of multiple signal transduction pathways is required for the HIF-1-mediated induction of VEGF expression in colon cancer cells exposed to PGE(2).
 ...
PMID:Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. 1272 58

Recently, the anti-tumor activity of N-myc downstream-regulated gene 2 (NDRG2) was elucidated, but the molecular mechanism of how NDRG2 works as a tumor suppressor is not well known. To determine the function of NDRG2 as a tumor suppressor, we established stable cell lines expressing NDRG2 protein or its mutant forms, and studied their effects on tumor cell growth. Interestingly, constitutive expression of wild-type NDRG2 induced the growth retardation of SW620 colon carcinoma cells. Introduction of NDRG2 into SW620 cells induced the decrease of c-Jun phosphorylation at Ser63, followed by the attenuation of activator protein-1 (AP-1) function as a transcriptional activator. Subsequently, the down-regulation of cyclin D1, which is known as a major target for AP-1 transcription activator, resulted in cell cycle arrest at G1/S phase. Additionally, treatment of NDRG2-siRNA on NDRG2-expressing cells has induced the recovery of c-Jun phosphorylation and cyclin D1 expression. Cell proliferation of those cells was also increased compared with untreated cells. NDRG2 mutants of which the phosphorylation sites at C-terminal region were removed by deletion or site-directed mutagenesis have shown no effect on cyclin D1 expression and could not induce cell growth retardation. In conclusion, NDRG2 modulates intracellular signals to control cell cycle through the regulation of cyclin D1 expression via phosphorylation pathway.
 ...
PMID:NDRG2 suppresses cell proliferation through down-regulation of AP-1 activity in human colon carcinoma cells. 1884 21

ARNTL2 is a transcriptional activator implicated in the molecular clock feedback system and is overexpressed in some malignant tumors. This study aimed to detect the effects of ARNTL2 knockdown by siRNA on the proliferation and invasion of colon carcinoma and clarify the molecular mechanisms of ARNTL2 in the development of colon carcinoma (CC). The CC microarray dataset GSE50760 was downloaded from the Gene Expression Omnibus (GEO) database. The expression levels of ARNTL2 in CC tissues and cancer cells were analyzed by immunohistochemistry and western blot, respectively. The knockdown of ARNTL2 expression was induced by RNA interference in colon cancer cells. The proliferation was detected by Cell Counting Kit-8 and clonal formation assays. The invasion and migration in vitro were detected by wound healing and transwell assays. Besides, a tumorigenicity test in the nude mice was performed to confirm whether ARNTL2 expression promoted the proliferation and invasion of CC cells. Furthermore, the expression of epithelial-mesenchymal transition (EMT) and PI3K/AKT signaling pathway-related factors were analyzed by western blot. Results showed that bioinformatics analysis found that ARNTL2 was upregulated in CC tissues. ARNTL2 was highly expressed in tissues and CC cells. Knockdown of ARNTL2 inhibited CC cells viability, colony formation, migration activity and reduced the size of tumors in the nude mice. Moreover, knockdown of ARNTL2 suppressed the expression of SMOC2, which may be the target gene of ARNTL2, and simultaneously inhibited the expression of EMT and PI3K/AKT signaling pathway-related factors. Taken together, downregulation of ARNTL2 could suppress CC cell proliferation and migration via SMOC2-EMT through inactivation of PI3K/AKT signaling pathway.
 ...
PMID:ARNTL2 knockdown suppressed the invasion and migration of colon carcinoma: decreased SMOC2-EMT expression through inactivation of PI3K/AKT pathway. 3235 42