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Transcription Factor Sp1 (transcription + factor_sp1)
Selected AbstractsTranscription factor Sp1 dysregulation in Alzheimer's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2008Bruce A. Citron Abstract Altered gene expression occurs in central nervous system disorders, including Alzheimer's disease (AD). Transcription factor Sp1 may be involved insofar as it can regulate the expression of several AD-related proteins, including amyloid precursor protein (APP) and tau. Sp1 could itself be regulated by inflammatory and other factors associated with AD, such as interleukin-1,. We measured an almost threefold elevation in the number of mRNA molecules of this cytokine in the AD frontal cortex. Sp1 mRNA was found to be up-regulated in these AD brains (along with Sp1-regulated COX-2), and the Sp1 increase was also seen at the protein level by Western immunoblotting. To determine whether this would also occur in transgenic mice developing AD pathology, we examined the expression of Sp1 in the cortex and hippocampus and observed higher levels of Sp1 mRNA and protein. These results indicate that elements of regulatory pathways involving transcription factor Sp1 may be useful targets for therapeutic intervention to prevent or reverse AD. © 2008 Wiley-Liss, Inc. [source] Transcription factor Sp1 regulates expression of cancer-associated molecule CD147 in human lung cancerCANCER SCIENCE, Issue 6 2010Ling-Min Kong CD147 is a novel cancer-associated biomarker that plays an important role in the invasion and metastasis of human lung cancer. In spite of its many known functions, little is known about CD147 transcriptional regulation. In this study, we explored the regulation of CD147 in human lung cancer tissues. Over 60% of the human lung cancer tissues expressed differential high levels of CD147. We then cloned the 5,-flanking region of the human CD147 gene and identified a critical promoter region at ,108 to ,42 which contained one binding site for Sp1, which was essential in up-regulating CD147 promoter activity. These results were proven by blocking Sp1 using RNAi or mithramycin A treatment and up-regulating Sp1 using transfection with eukaryotic expression vector. Consistent with the CD147 transcription activation, a high level of Sp1 expression was detected in lung cancer cell lines overexpressing CD147. Chromatin immunoprecipitation assay showed that much more Sp1 could bind to the CD147 promoter in 95-D with CD147 high expression than in SK-MES-1 with CD147 low expression. There was a significant positive correlation between CD147 expression and Sp1 expression level detected by immunohistochemistry (r = 0.831). Collectively, our results suggest that Sp1 is essential for regulating the CD147 gene expression in human lung cancer. (Cancer Sci 2010) [source] Hormonal regulation of multiple promoters of the rat mitochondrial glycerol-3-phosphate dehydrogenase geneFEBS JOURNAL, Issue 14 2001Identification of a complex hormone-response element in the ubiquitous promoter B Rat mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is regulated by multiple promoters in a tissue-specific manner. Here, we demonstrate that thyroid hormone (3,5,3,-tri-iodo- l -thyronine) and steroid hormone but not the peroxisome proliferator clofibrate and retinoic acid stimulate the activation of the ubiquitous promoter B in a receptor-dependent manner, whereas the more tissue-restricted promoters A and C are not inducible by these hormones. Thyroid hormone action is mediated by a direct repeat +4 (DR+4) hormone-response element as identified by deletion and mutation analyses of promoter B in transient transfection analyses. The DR+4 element was able to bind to an in vitro translated thyroid hormone receptor in band-shift and supershift experiments. The hormone-response element comaps with a recognition site for the transcription factor Sp1, suggesting complex regulation of this sequence element. Mutation of this Sp1-recognition site reduces the basal promoter B activity dramatically in HepG2 and HEK293 cells in transient transfection and abolishes the binding of Sp1 in band-shift experiments. As demonstrated by Western-blot experiments, administration of tri-iodothyronine to euthyroid rats increases hepatic mGPDH protein concentrations in vivo. As it has recently been reported that human mGPDH promoter B is not regulated by tri-iodothyronine, this is the first example of a differentially tri-iodothyronine-regulated orthologous gene promoter in man and rat. [source] Role of O -linked ,- N -acetylglucosamine modification in the subcellular distribution of alpha4 phosphoprotein and Sp1 in rat lymphoma cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Shauna M. Dauphinee Abstract The mTOR alpha4 phosphoprotein is a prolactin (PRL)-downregulated gene product that is found in the nucleus of PRL-dependent rat Nb2 lymphoma cells. Alpha4 lacks a nuclear localization signal (NLS) and the mechanism of its nuclear targeting is unknown. Post-translational modification by O -linked ,- N -acetylglucosamine (O -GlcNAc) moieties has been implicated in the nuclear transport of some proteins, including transcription factor Sp1. The nucleocytoplasmic enzymes O -,- N -acetylglucosaminyltransferase (OGT) and O -,- N -acetylglucosaminidase (O -GlcNAcase) adds or remove O -GlcNAc moieties, respectively. If O -GlcNac moieties contribute to the nuclear targeting of alpha4, a decrease in O -GlcNAcylation (e.g., by inhibition of OGT) may redistribute alpha4 to the cytosol. The present study showed that alpha4 and Sp1 were both O -GlcNAcylated in quiescent and PRL-treated Nb2 cells. PRL alone or PRL,+,streptozotocin (STZ; an O -GlcNAcase inhibitor) significantly (P,,,0.05) increased the O -GlcNAc/alpha4 ratio above that in control quiescent cells. However, PRL,+,alloxan (ALX; an OGT inhibitor) or ALX alone did not decrease O -GlcNAcylation of alpha4 below that of controls and alpha4 remained nuclear. In comparison, PRL (±ALX/STZ) greatly increased Sp1 protein levels, caused a significant decrease in the GlcNAc/Sp1 ratio (P,,,0.05, n,=,3) as compared to controls and partially redistributed Sp1 to the cytosol. Finally, a 50% downregulation of OGT gene expression by small interfering RNA (i.e., siOGT) partially redistributed both alpha4 and Sp1 to the cytosol. The alpha4 protein partner PP2Ac had no detectable O -GlcNAc moieties and its nuclear distribution was not affected by siOGT. In summary, alpha4 and Sp1 contained O -GlcNAc moieties, which contributed to their nuclear targeting in Nb2 cells. © 2005 Wiley-Liss, Inc. [source] Transcription factor Sp1 dysregulation in Alzheimer's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2008Bruce A. Citron Abstract Altered gene expression occurs in central nervous system disorders, including Alzheimer's disease (AD). Transcription factor Sp1 may be involved insofar as it can regulate the expression of several AD-related proteins, including amyloid precursor protein (APP) and tau. Sp1 could itself be regulated by inflammatory and other factors associated with AD, such as interleukin-1,. We measured an almost threefold elevation in the number of mRNA molecules of this cytokine in the AD frontal cortex. Sp1 mRNA was found to be up-regulated in these AD brains (along with Sp1-regulated COX-2), and the Sp1 increase was also seen at the protein level by Western immunoblotting. To determine whether this would also occur in transgenic mice developing AD pathology, we examined the expression of Sp1 in the cortex and hippocampus and observed higher levels of Sp1 mRNA and protein. These results indicate that elements of regulatory pathways involving transcription factor Sp1 may be useful targets for therapeutic intervention to prevent or reverse AD. © 2008 Wiley-Liss, Inc. [source] Roles of the conserved CCAAT and GC boxes of the human and mouse type II transforming growth factor-, receptor genesMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 4 2003Cory T. Bernadt Abstract Embryonal carcinoma (EC) cells are used widely to study the molecular mechanisms that regulate the transcription of genes during mammalian embryogenesis. The type II transforming growth factor-, receptor (T,R-II) gene is expressed at very low levels by mouse EC cells prior to differentiation. Differentiation of EC cells results in increases of both the steady-state levels of T,R-II mRNA and the activity of the T,R-II promoter. Several cis -regulatory elements have been shown previously to regulate the T,R-II gene. This study focuses on the role of a CCAAT box and three GC boxes in the regulation of the human and mouse T,R-II promoters in EC-differentiated cells. We demonstrate that the CCAAT box and two flanking GC boxes, Sp A and Sp B, function as positive regulatory elements in the human T,R-II promoter, and that the transcription factor complex NF-Y positively regulates the human T,R-II promoter through the CCAAT box motif. We also show that the CCAAT box and the downstream GC box Sp B, which are conserved between the human and mouse promoters, behave as positive regulatory elements in the mouse T,R-II promoter. In addition, we demonstrate that the transcription factor Sp1 can bind to the Sp B GC box in vitro. Finally, we show that a GC box located 25 bp upstream of the major transcription start site of the T,R-II gene plays a minimal role in the function of the T,R-II promoter in EC-differentiated cells. Together, our studies highlight important differences and similarities in the cis -regulatory elements that regulate the human and mouse T,R-II promoters. Mol. Reprod. Dev. 65: 353,365, 2003. © 2003 Wiley-Liss, Inc. [source] Regulation of transcription of the Dnmt1 gene by Sp1 and Sp3 zinc finger proteinsFEBS JOURNAL, Issue 12 2002Shotaro Kishikawa The Sp family is a family of transcription factors that bind to cis -elements in the promoter regions of various genes. Regulation of transcription by Sp proteins is based on interactions between a GC-rich binding site (GGGCGG) in DNA and C-terminal zinc finger motifs in the proteins. In this study, we characterized the GC-rich promoter of the gene for the DNA methyltransferase (Dnmt1) that is responsible for methylation of cytosine residues in mammals and plays a role in gene silencing. We found that a cis -element (nucleotides ,161 to ,147) was essential for the expression of the mouse gene for Dnmt1. DNA-binding assays indicated that transcription factors Sp1 and Sp3 bound to the same cis -element in this region in a dose-dependent manner. In Drosophila SL2 cells, which lack the Sp family of transcription factors, forced expression of Sp1 or Sp3 enhanced transcription from the Dnmt1 promoter. Stimulation by Sp1 and Sp3 were independent phenomena. Furthermore, cotransfection reporter assays with a p300-expression plasmid revealed the activation of the promoter of the Dnmt1 gene in the presence of Sp3. The transcriptional coactivator p300 interacted with Sp3 in vivo and in vitro. Our results indicate that expression of the Dnmt1 gene is controled by Sp1 and Sp3 and that p300 is involved in the activation by Sp3. [source] Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neuronsANNALS OF NEUROLOGY, Issue 3 2001Sukalyan Chatterjee PhD Global inhibitors of RNA or protein synthesis such as actinomycin D or cycloheximide abrogate neuronal apoptosis induced by numerous pathological stimuli in vitro and in vivo. The clinical application of actinomycin D or cycloheximide to human neurological disease has been limited by the toxicities of these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins, while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G-C-rich regions of promoters. Here we demonstrate that mithramycin A and its structural analog chromomycin A3 are potent inhibitors of neuronal apoptosis induced by glutathione depletion-induced oxidative stress or the DNA-damaging agent camptothecin. We correlate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 and Sp3 to their cognate "G-C" box induced by oxidative stress or DNA damage. The protective effects of mithramycin A cannot be attributed to global inhibition of protein synthesis. Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics. Ann Neurol 2001;49:345,354 [source] | |||||||||||||