Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00631 (Gel)
 14,881 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein phosphatase 1 and 2A inhibitor, okadaic acid, has been shown to stimulate many cellular functions by increasing the phosphorylation state of phosphoproteins. In human monocytes, okadaic acid by itself stimulates tumor necrosis factor alpha (TNF-alpha) mRNA accumulation and TNF-alpha synthesis. Calyculin A, a more potent inhibitor of phosphatase 1, has similar effects. TNF-alpha mRNA accumulation in okadaic acid-treated monocytes is due to increased TNF-alpha mRNA stability and transcription rate. The increase in TNF-alpha mRNA stability is more remarkable in okadaic acid-treated monocytes than the mRNA stability of other cytokines, such as interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6. Gel retardation studies show the stimulation of AP-1, AP-2, and NF-kappa B binding activities in okadaic acid-stimulated monocytes. This increase may correlate with the increase in TNF-alpha mRNA transcription rate. In addition to the stimulation of TNF-alpha secretion by monocytes, okadaic acid appears to modulate TNF-alpha precursor processing, as indicated by a marked increase in the cell-associated 26-kD precursor. These results suggest that active basal phosphorylation/dephosphorylation occurs in monocytes, and that protein phosphatase 1 or 2A is important in regulating TNF-alpha gene transcription, translation, and posttranslational modification.
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PMID:Stimulation of tumor necrosis factor alpha production in human monocytes by inhibitors of protein phosphatase 1 and 2A. 132 71

We previously studied the transcriptional mechanisms involved in expression of the murine nerve growth factor (NGF) gene. To investigate the regulation of transcription of the human NGF gene, the promoter region was cloned. The nucleotide sequences of the human and mouse genes are greater than 90% similar near their promoters. The cloned human promoter was transcriptionally active in mouse L929 fibroblasts. 5' Deletion analyses indicated that the -85 to -45 region stimulates basal transcription 6-fold. This segment is greater than 80% identical in human and mouse genes except for an AP-1 consensus sequence found only in the human gene. A second AP-1 consensus sequence at +34, previously shown to function as a regulatory element in the mouse gene, is identical in both genes. Gel shift analyses of L929 cell extracts revealed binding of protein to oligonucleotide probes spanning each of the two AP-1 consensus sequences of the human gene. The gel shift patterns differed, suggesting interaction of different proteins with the two probes. Our results demonstrate that the human NGF gene promoter is transcriptionally active in mouse fibroblasts, and implicate an upstream region in basal transcription.
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PMID:The human nerve growth factor gene: structure of the promoter region and expression in L929 fibroblasts. 133 71

The effects of glucocorticoid hormones on the expression of the growth factor-inducible genes JE, KC, and c-myc were analyzed in parental BALB/3T3 and polyomavirus middle-T antigen-transfected cell lines. Northern (RNA) blot hybridization and run-on transcription analysis showed that (i) glucocorticoid hormones selectively inhibit JE and KC expression at the transcriptional level and (ii) the downregulatory effect of glucocorticoids on JE and KC expression is partial for serum-stimulated and middle T antigen-transformed cells and total for quiescent and exponentially growing cells. Gel mobility assays using AP-1 oligonucleotides showed a positive correlation between glucocorticoid downregulating effect and presence of the AP-1 complex. JE and KC downregulation by means of the AP-1 complex may play a role in the actions of glucocorticoids as anti-inflammatory and antitumor agents. The ability of glucocorticoids to downregulate JE and KC was used to investigate the relevance of these genes to the mitogenic response to serum growth factors. Hydrocortisone did not alter the basal DNA synthesis level displayed by quiescent 3T3 cells, but it potentiated both the mitogenic effect of platelet-derived growth factor and c-myc induction by serum growth factors. Upon serum restimulation, untreated and dexamethasone-treated quiescent 3T3 cultures entered the S phase after an identical time lag (G1). These results suggest that (i) JE and KC are not necessary for the G0----G1----S transition and (ii) c-myc overexpression is likely to be the basis for the potentiating effect of glucocorticoids on serum growth factors.
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PMID:Downregulation of JE and KC genes by glucocorticoids does not prevent the G0----G1 transition in BALB/3T3 cells. 140 51

HL-60 cells isolated for resistance to vincristine are multidrug resistant and defective in the cellular accumulation of drug. Further studies demonstrate that these cells are also highly defective in 12-O-tetradecanoylphorbol-13-acetate (TPA) induced differentiation to macrophages. Analysis of this system demonstrates that certain protooncogenes which may contribute to differentiation are expressed at similar levels in sensitive and resistant cells. Thus, treatment of cells with TPA results in a reduction in the levels of c-myb and c-myc mRNA, while the expression of c-fos, c-jun, and junB is greatly enhanced. Immunoprecipitation experiments also demonstrate a TPA induced increase in the c-jun protein in both sensitive and resistant cells. Gel mobility shift assays show that TPA induces AP-1 formation in sensitive cells, whereas in parallel experiments with the HL-60/Vinc isolate, AP-1 is essentially absent. It has been found, however, that in resistant cells which have reverted to drug sensitivity, the levels of TPA inducible AP-1 is essentially identical to that of sensitive cells. Revertant and sensitive cells differentiate at similar levels in the presence of TPA. These studies therefore demonstrate that HL-60/Vinc cells are defective in the TPA induction of a functional AP-1 complex and that this may account for the inability of these cells to differentiate to macrophages. The molecular basis of the finding that AP-1 is not formed in resistant cells remains to be determined.
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PMID:HL-60 cells isolated for resistance to vincristine are defective in 12-O-tetradecanoylphorbol-13-acetate induced differentiation and the formation of a functional AP-1 complex. 145 Apr 90

We cloned, sequenced and characterized a promoter region of the mouse homologue of the Alzheimer's disease amyloid precursor protein (APP)-encoding gene. The promoter region is highly homologous to that of the human APP (hAPP) gene. It has a high G+C content, lacks typical 'TATA' and 'CAAT' boxes, and contains possible binding sites for AP-1, heat-shock factor, Sp1 and AP-4. The promoter region was fused with the cat reporter gene, and the fusion genes were transfected to both the NB41A3 (mouse neuroblastoma) and L-cell lines. The promoter activity was monitored by chloramphenicol acetyltransferase (CAT) activity in a transient expression assay. The promoter was equally active in both cell lines. The deletion analysis revealed that there existed a negative regulatory element(s) between -153 and -100 bp and a positive element(s) between -100 and -37 bp. The negative element was shown to suppress the transcriptional activity of heterologous simian virus 40 promoter. DNase I footprinting experiments revealed that three nuclear protein-binding sites existed in the regulatory region, one in the negative and two in the positive regulatory regions. Gel retardation assay showed that Sp1 was one of the factors binding to the positive regulatory region. A nuclear factor binding to the negative regulatory region seemed to be missing in brain.
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PMID:Positive and negative regulatory elements for the expression of the Alzheimer's disease amyloid precursor-encoding gene in mouse. 155 68

Phorbol 12-myristate 13-acetate induces a 3- and 10-fold induction of chloramphenicol acetyltransferase (CAT) activity in HT1080 and HeLa cells, respectively, following transient transfection of a 336-base pair plasminogen activator inhibitor-1 (PAI-1) promoter fragment linked to a CAT reporter gene. Substitution mutations in the regions encompassing nucleotides -78 to -69 (TGGGTGGGGC) or -61 to -54 (TGAGTTCA), but not in the regions -155 to -149 (TGCCTCA) or -84 to -76 (AGTGAGTGG) reduced this induction. Gel electrophoresis of double-stranded -65 to -50 oligonucleotides of the PAI-1 promoter region and nuclear extracts from Hela cells produced a gel shift pattern similar to that obtained with a AP-1 consensus oligomer, and excess unlabeled AP-1 oligomer reverted binding, suggesting that this region of the PAI-1 promoter is an AP-1-like binding site. Gel electrophoresis of double-stranded -82 to -65 oligonucleotides with HeLa nuclear extracts revealed a gel shift pattern of three bands; Sp1 consensus oligomer competed with the binding to two of these bands and AP-2 consensus sequence oligomer with the binding to the third band. The -82 to -65 oligomer also bound to purified AP-2 and Sp1 proteins. Southwestern blotting of HeLa nuclear extracts revealed that the labeled oligomer spanning region -82 to -65 bound to proteins with molecular masses of 52 and 72 kDa. Consensus AP-2 oligonucleotides competed for binding of the labeled -82 to -65 oligonucleotide to the 52-kDa protein, but consensus Sp-1 oligonucleotides did not compete for binding to the 72-kDa compound. The 72-kDa component binding to the -82 to -65 region may represent a new protein involved in transcriptional regulation.
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PMID:Interaction of AP-1-, AP-2-, and Sp1-like proteins with two distinct sites in the upstream regulatory region of the plasminogen activator inhibitor-1 gene mediates the phorbol 12-myristate 13-acetate response. 163 45

Resistance to radiation leukemia virus-induced leukemia is mediated by gene(s) in the H-2D region of the MHC; a clear correlation exists between disease resistance and increased H-2Dd expression on the thymocyte surface. We have investigated the molecular basis for this stimulation of H-2Dd class I expression. Elevated H-2 mRNA and H-2 transcription are demonstrated in the infected thymocytes as compared to normal thymocytes indicating that the elevation of H-2 surface expression is the result of transcriptional activation. Gel mobility assays performed with nuclear extracts of normal and infected thymocytes and sequences 5' of the H-2Dd gene show that specific binding occurs with both extracts; the binding differs both quantitatively and qualitatively, however. DNase I protection analysis detects a protein binding site that is protected only by extracts from infected cells. The protected region contains a sequence similar to the AP-1 consensus sequence. Gel shift competition assays and UV photo-cross-linking to an oligonucleotide containing this sequence demonstrate that specific binding of an H-2 binding factor 1 occurs and that this factor is not the AP-1 binding complex. This novel binding factor, activated in vivo, might also be involved in the normal regulation of H-2 gene expression by recognizing the highly conserved binding sequence (TGACGCG) found in the 5' flanking region of many MHC class I genes. This is the first demonstration of the parallel stimulation of a DNA binding activity and increased transcription occurring in thymocytes after infection with a leukemogenic retrovirus.
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PMID:A novel DNA binding activity is elevated in thymocytes expressing high levels of H-2Dd after radiation leukemia virus infection. 163 76

Our previous studies showed that the AP-1 recognition element (ARE) present within the SV40 72-base pair (bp) enhancer will activate transcription in yeast when placed upstream of a truncated CYC1 promoter. However, the AP-2/AP-3 recognition element (also known as the core sequence TGTGGAAAG) from the SV40 enhancer was not able to activate CYC1-dependent transcription. In this report, we show that the core sequence, when cloned next to a yeast UAS (upstream activation sequence), can inhibit the transcriptional stimulatory activity of the UAS. We refer to this sequence as the upstream repressor element (URE) in yeast. Repression occurs in an orientation-independent fashion and irrespective of the placement of the URE between the UAS and TATA box or upstream of both of these elements. Furthermore, repression is seen when the URE is separated from the UAS by up to 214 bp. Interestingly, multiple copies of an activator site can overcome this repression. Gel-shift analysis and URE-probed proteins blots indicate the presence of two polypeptide chains capable of binding the URE in yeast. The experimental evidence suggests that either the repression associated with the URE sequence is mediated by a direct, one-to-one interaction between the proteins recognizing the URE and GCRE, or alternatively, that there is a direct interaction between the activator and repressor for a general transcription factor.
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PMID:The SV40 core sequence functions as a repressor element in yeast. 165 62

The transcriptional mechanisms which contribute to the regulation of nerve growth factor (NGF) production are still largely unknown. We previously expressed the NGF promoter region in transgenic mice to localize cis regulatory elements to within 5 kb of the promoter. To further map these elements, and to begin to study the corresponding transacting factors, we here assayed the effects of 5' deletions and point mutations and examined the binding of nuclear factors to the NGF promoter region using L929 cell fibroblasts. Sequential deletions delineated regions upstream from the promoter which stimulated and inhibited transcription. DNAse-1 footprinting experiments identified four upstream segments, designated F2, F4, F6 and F8, which bound L929 cell nuclear proteins. F2 and F4 mapped to stimulatory and F6 and F8 to inhibitory regions. Competition experiments using a heptanucleotide present in both F2 and F4 segments suggested that they may be bound by related factors. Gel shift assays showed that the F8 binding proteins are less abundant in L929 cells than in NIH 3T3 fibroblasts and B16 melanoma cells. In addition to the upstream segments, a downstream AP-1 consensus sequence bound L929 nuclear proteins. Mutation of the AP-1 consensus sequence eliminated binding of nuclear proteins and reduced transcriptional activity. Our results indicate that transcriptional activator as well as suppressor regions surround the NGF gene promoter. The regulation of NGF production is likely to involve cis elements within these regions and transacting factors that bind to them.
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PMID:Structural and functional identification of regulatory regions and cis elements surrounding the nerve growth factor gene promoter. 166 23

During the course of lytic infection by simian virus 40 (SV40), expression of both the viral late genes and certain host cellular genes is induced. The promoter of the cellular transferrin receptor (TR) gene contains a DNA sequence which is similar to the AP-1- and AP-4-binding region in SV40 which has been implicated in the control of the viral late promoter. Expression of TR is needed for cells to enter S-phase and is therefore expected to be important for the SV40 lytic cycle. Here we show that the level of TR mRNA in vivo was increased by SV40 infection. A factor which activates transcription from the TR promoter in vitro was specifically induced in SV40-infected cells. Gel mobility shift assays with an oligonucleotide comprising this part of the TR promoter showed three nucleoprotein complexes to be formed with proteins from CV-1 cells. Following SV40 infection, one of the complexes was increased ten-fold. Formation of this complex was specifically reduced by competition with the phorbol ester-responsive element of the collagenase gene, implying that the factor is a member of the AP-1/Jun/Fos family. Cross-linking of the complex by ultraviolet light showed major DNA-binding components to be proteins of about 55 kD and 47 kD. Removal of this factor by adding the oligonucleotide to in vitro transcription reactions with the TR promoter, abolished the activation of TR transcription. The factor which binds to the TR promoter co-sedimented with SV40 chromosomes extracted late in infection. This suggests that similar transcriptional regulatory proteins are involved in controlling transcription from both the SV40 and the TR promoters, and that the virus can use a common mechanism to induce viral and host cellular transcription.
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PMID:SV40 activates transcription from the transferrin receptor promoter by inducing a factor which binds to the CRE/AP-1 recognition sequence. 166 7


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