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At least 1,009 records · Page 56Linked to original sources
PubMed2000

TFE3, a transcription factor homologous to microphthalmia, is a potential transcriptional activator of tyrosinase and TyrpI genes.

Microphthalmia gene encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor involved in the development of the melanocyte lineage and plays a key role in the transcriptional regulation of the melanogenic enzymes, tyrosinase and TyrpI. Recently, we have shown that Microphthalmia mediates the melanogenic effects elicited by alphaMSH that up-regulates the expression of tyrosinase through the activation of the cAMP pathway. Therefore, Microphthalmia appears as a principal gene in melanocyte development and functioning. Among the transcription factors of the bHLH-Zip family, TFE3 and TFEB show a remarkably elevated homology with Microphthalmia. These observations prompted us to investigate the role of TFE3 and TFEB in the regulation of tyrosinase and TyrpI gene transcription. We show in this report that overexpression of TFE3 stimulates the tyrosinase and TyrpI promoter activities, while TFEB acts only on the TyrpI promoter. TFE3 and TFEB elicit their effects mainly through the binding to Mbox (AGTCATGTGCT) and Ebox motifs (CATGTG) of tyrosinase and TyrpI promoters. In B16 melanoma cells, the high basal expression of TFE3 is down-regulated by forskolin and by alphaMSH. Interestingly, endogenous TFE3 cannot bind as homodimers to the Mbox, and we did not detect TFE3/Mi heterodimers. According to these data, TFE3 is clearly endowed with the capacity to regulate tyrosinase and TyrpI gene expression. However, TFE3 binding to the melanogenic gene promoters is hindered, thereby preventing its potential melanogenic action. In specific physiological or pathological conditions, the recovery of its binding function would make TFE3 an important element in melanogenesis regulation.

3T3 Cells↗
PubMed2001

Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1.

Cytokines and glucocorticoids (GCs) signaling pathways interfere with each other in the regulation of apoptosis and gene expression in the immune system. Interleukin-2 (IL-2), through the Janus kinase/signal transducers and activators of transcription (Jak/STAT) and mitogen-activated protein kinase (MAPK) pathways, activates STAT5 and activated protein-1 (AP-1) transcription factors, respectively, which are known to repress glucocorticoid receptor (GR) activity, at least in part, through protein-protein interactions. In this work, we have analyzed the mechanisms whereby IL-2 down-regulates the GC-induced transactivation of the mouse mammary tumor virus long terminal repeat (MMTV-LTR) in murine CTLL-2 T lymphocytes. Mutagenesis studies revealed that the MMTV-LTR STAT5 binding site (-923/-914) was not required for IL-2-mediated inhibition but identified both glucocorticoid response elements (GREs) and the -104/+1 region as critical elements for this negative response. The DNA binding activities of transcription factors required for GC-mediated activation of the MMTV-LTR promoter and that bind to the -104/+1 region (nuclear factor-1, Oct-1) were not affected by IL-2 treatment. Overexpression of wild-type STAT5B enhanced the effect of IL-2 on MMTV-LTR activity, and a dominant negative form of STAT5B (Y699F) abolished the IL-2-mediated MMTV-LTR inhibition, whereas AP-1 activation had no effect in this system. Direct interaction between liganded GR and STAT5 was observed in CTLL-2 cells in a STAT5 phosphorylation-independent manner. Overexpression of nuclear coactivators CBP (CREB-binding protein) or SRC-1a (steroid receptor coactivator 1a) did not blunt IL-2 inhibitory effects. We suggest that the STAT5-repressive activity on the GC-dependent transcription may involve direct interaction of STAT5 with GR, is dependent on the promoter context and STAT5 activation level, and occurs independently of coactivators levels in T cells.

Animals↗
PubMed2001

Transcriptional regulation of the bcl-x gene encoding the anti-apoptotic Bcl-xL protein by Ets, Rel/NFkappaB, STAT and AP1 transcription factor families.

Transcription factors play an essential role in determining the fate of a cell by affecting the expression of target genes involved in proliferation, in differentiation and in programmed cell death. Under certain conditions, some of these factors are capable of deregulating expression of genes involved in the cell cycle and/or in programmed cell death resulting in uncontrolled proliferation of the cell. The focus of this review is on the transcriptional regulation of the bcl-x gene encoding the anti-apoptotic Bcl-xL protein. Since 1999, several papers have implicated members of the Ets, Rel/NFkappaB, STAT and AP-1 families as transcription factors regulating bcl-x expression. A specific emphasis of these different transcription factor families on bcl-x regulation in hematopoietic cells is discussed.

Animals↗
PubMed2005

NF-kappaB contributes to transcription of placenta growth factor and interacts with metal responsive transcription factor-1 in hypoxic human cells.

Placenta growth factor (PlGF) is a member of the vascular endothelial growth factor family of cytokines that control vascular and lymphatic endothelium development. It has been implicated in promoting angiogenesis in pathological conditions via signaling to vascular endothelial growth factor receptor-1. PlGF expression is induced by hypoxia and proinflammatory stimuli. Metal responsive transcription factor 1 (MTF-1) was shown to take part in the hypoxic induction of PlGF in Ras-transformed mouse embryonic fibroblasts. Here we report that PlGF expression is also controlled by NF-kappaB. We identified several putative binding sites for NF-kappaB in the PlGF promoter/enhancer region by sequence analyses, and show binding and transcriptional activity of NF-kappaB p65 at these sites. Expression of NF-kappaB p65 from a plasmid vector in HEK293 cells caused a substantial increase of PlGF transcript levels. Furthermore, we found that hypoxic conditions induce nuclear translocation and interaction of MTF-1 and NF-kappaB p65 proteins, suggesting a role for this complex in hypoxia-induced transcription of PlGF.

Animals↗
PubMed2003

The retinoblastoma protein-associated transcription repressor RBaK interacts with the androgen receptor and enhances its transcriptional activity.

In search of potential androgen receptor coregulators we performed a yeast two-hybrid screening using the androgen receptor ligand-binding domain as bait and a human prostate cDNA library as prey and found that the carboxy-terminal domain of retinoblastoma-associated Krüppel protein (RbaK), a member of the Krüppel zinc finger protein family, interacts in a ligand-dependent way with the ligand-binding domain of the androgen receptor. RBaK was recently identified as a transcriptional regulator that interacts with the retinoblastoma protein and thereby influences E2F regulated transcription. The interaction of RBaK with the androgen receptor was further documented using mammalian two-hybrid experiments, in vitro binding studies and coimmunoprecipitation. Finally, we demonstrated that both RBaK and the retinoblastoma protein coactivate androgen receptor-mediated transcription in cotransfection experiments. In conclusion, our data show that RBaK interacts with the androgen receptor and increases its transcriptional activity. Moreover, the double interaction of RBaK with the retinoblastoma protein and with the androgen receptor provides a novel link between the androgen receptor and the regulation of the cell cycle.

Animals↗
PubMed1992

The human immunodeficiency virus tat protein increases the transcription of human Alu repeated sequences by increasing the activity of the cellular transcription factor TFIIIC.

The HIV Tat protein is able to upregulate the transcription by RNA polymerase III of cotransfected or endogenous cellular Alu-repeated sequences in both HeLa and Jurkat T cells. This effect is mediated by an increase in the activity of transcription factor TFIIIC, which binds to the B box in the RNA polymerase III Alu promoter. This is the first example of an effect of the Tat protein on the transcription of a cellular gene or on the activity of a cellular transcription factor. The significance of this effect for the life cycle of HIV and its interaction with infected cells is discussed.

Actins↗
PubMedDate not supplied

Transcriptional activation of the bcl-2 apoptosis suppressor gene by the paired box transcription factor PAX8.

The bcl-2 proto-oncogene suppresses apoptosis in a variety of cell types and is essential for normal renal development. PAX8 is a member of the paired box class of transcription factors and is developmentally regulated. bcl-2 and PAX8 are both expressed in the kidney during development and throughout life, demonstrating a nearly identical pattern of expression. We used transient transfection reporter assays and electrophoretic mobility shift assays to test PAX8 transcriptional regulation of bcl-2. PAX8 transcriptionally activates the bcl-2 promoter and binds to promoter sequences in vitro. These findings establish that PAX8 can transcriptionally regulate bcl-2 and suggest that suppression of apoptosis is an important event in the development and maintenance of renal tubular epithelial structures.

Apoptosis↗
PubMed2002

Transcriptional and post-transcriptional mechanisms of glucocorticoid antiproliferative effects.

Glucocorticoids (GCs) are used as immunosuppressive and anti-inflammatory agents in treating organ transplantation rejection, autoimmune diseases, (hematological) cancers, and inflammatory disorders. GCs exert their effects through a multitude of mechanisms, the most significant of which is inhibition of cytokine production, and for some cytokines their effects on target cells. Paradoxically, GCs also upregulate the expression of (pro-inflammatory) high-affinity cytokine receptors on target cells in the face of lost ligand (cytokine) stimulation. GC inhibition of cytokine expression occurs at both transcriptional and post-transcriptional levels. GCs acted transcriptionally by binding their cytosolic receptor (GR), thereby facilitating its nuclear translocation and subsequent binding to the promoter region of cytokine genes on sites compatible with GC response element (GRE) motifs, which in turn directly or indirectly regulated gene expression. In addition to direct DNA binding, GCs acted post-transcriptionally by: (1) antagonism of nuclear factors required for efficient gene expression either directly or through induction of the expression of specific transcription factor antagonists, (2) altered Th lineage development by favouring the generation of (anti-inflammatory) Th2 cells and suppressing the induction or the activity of established (pro-inflammatory) Th1 cells, and (3) stimulating the expression of transforming growth factor (TGF)-beta, an immunosuppressive cytokine which inhibited cytokine production. However, these mechanisms are not mutually exclusive, since GCs may utilize more than one mechanism in exerting their anti-proliferative effect.

Cell Division↗
PubMed1989

Mapping of Digitaria streak virus transcripts reveals different RNA species from the same transcription unit.

All, except 19 [corrected] bp, of the Digitaria streak virus (DSV) genome is transcribed. Two RNA transcripts (1+ and 2+) are encoded by the virion DNA strand and up to five (1- to 5-) by the complementary DNA strand [corrected]. Detailed mapping of these RNAs has revealed evidence for splicing in one species (RNA 4-), which together with its more abundant unspliced counterpart (RNA 2-) could synthesize both a 30.5 and 41 kd polypeptide from the same transcription unit. This extensive overlapping of spliced and unspliced RNAs could indicate that the initiation and splicing of transcripts is temporally regulated. At least one transcript (RNA 1-) may have a non-translational role. Transcription of the DSV genome shows similarities to some animal DNA viruses, particularly the papovaviruses.

Base Sequence↗
PubMed1992

Transcription mapping of a 100 kb locus of Plasmodium falciparum identifies an intergenic region in which transcription terminates and reinitiates.

We have mapped Plasmodium falciparum erythrocytic stage transcription units on chromosome 10 in the vicinity of the gene encoding the glycophorin binding protein (GBP130) using yeast artificial chromosomes (YACs). Three erythrocytic stage transcription units are clustered in a 40 kb region. Two of these genes are closely linked, separated by less than 2 kb. Nuclear run-on data demonstrate that transcription of these two genes, though unidirectional, is monocistronic. Within this intergenic region are the sites at which transcription of the upstream gene terminates and the GBP130 gene initiates. These studies represent the first description of the minimal and necessary cis-acting elements for transcription termination and initiation in this protozoan parasite.

Amino Acid Sequence↗
PubMed1993

A transcription factor with homology to the AP-1 family links RNA transcription and DNA replication in the lytic cycle of Epstein-Barr virus.

oriLyt, the lytic origin of DNA replication of Epstein-Barr virus (EBV), ensures viral DNA amplification during the productive or lytic phase of the virus' life cycle. To understand the contribution of cis- and transacting elements involved in DNA replication of oriLyt, a detailed mutational analysis was undertaken which defined BZLF1, a viral transcriptional activator, as an essential replication factor. The BZLF1 protein belongs to the extended fos/jun family of transcription factors and binds to specific BZLF1 binding motifs within oriLyt, as well as to consensus AP-1 sites. Recombinant, chimeric transcription factors identified the transcriptional activation domain of BZLF1 as being necessary to mediate DNA replication, a function which could not be substituted by any other transcription factor tested, including jun, E2, myc or VP16.

Binding Sites↗
PubMed1992

The third IGF-II promoter specifies transcription of three transcripts out of five in human placenta.

Insulin-like growth factor-II (IGF-II) mRNA exists as multiple transcript size classes, such as 6.0, 5.3, 4.9, 3.2, and 2.2 kb mRNAs in various human tissues. Three different promoters, 2 different polyadenylation sites, and alternative splicing are involved in producing these multiple transcripts. Initiation of transcription at the 3 different promoters results in multiple mRNAs which contain identical coding regions but different 5'-untranslated regions (5'-UTRs). The first promoter is thought to direct expression of 5.3 kb mRNA in adult human liver. The second promoter region directs expression of 6.0, 3.2, and 2.2 kb mRNAs in human fetal tissues and several adult nonliver tissues. The third promoter specifies transcription of a 4.9 kb mRNA in various tissues. We isolated and sequenced a cDNA clone (pIGF-II-1-70) from a human placental cDNA library, which contains the IGF-II coding region and the 5'-UTR associated with the third promoter. By using a 5'-UTR-specific probe from the clone, we found that this third 5'-UTR is contained in the IGF-II mRNA of 2.2 kb and is absent in the 3.2 kb IGF-II mRNA. We also found an 0.9 kb transcript expressed in placenta, which hybridized strongly to the third 5'-UTR specific probe but not to IGF-II coding region probes. This finding might indicate the existence of an mRNA encoding an IGF-II-associated peptide.

Base Sequence↗
PubMed1994

Structural analysis of transcripts for the protein L-isoaspartyl methyltransferase reveals multiple transcription initiation sites and a distinct pattern of expression in mouse testis: identification of a 5'-flanking sequence with promoter activity.

The gene encoding the protein L-isoaspartyl-(D-aspartyl) methyltransferase (protein carboxyl methyltransferase, PCMT) is widely expressed in bacteria and eucaryotic cells. An antisense probe encompassing the first exon of the murine PCMT gene [E. A. Romanik, C. L. Ladino, S. C. D'Ardenne, and C. M. O'Connor (1992) Gene 118, 217-222] was used in ribonuclease protection assays to identify the initiation sites for PCMT transcription in mouse testis, brain, and liver tissues. Two major initiation sites, 155-157 nucleotides (nt) and 119 nt upstream from the ATG initiation codon, were identified in all tissues in addition to several minor sites. The locations of the initiation sites in testicular RNA were confirmed using ligation-mediated 5'-rapid amplification of cDNA ends (RACE). These initiation sites are situated at the 3'-end of a 407-bp genomic sequence which is sufficient to drive the expression of a firefly luciferase gene in transient transfection assays with NIH/3T3 cells. The 407-bp sequence resembles a housekeeping gene promoter in its high G+C content, lack of a TATA box and the presence of multiple potential binding sites for the transcription factors Sp1 and ETF. Alternative splicing in the C-terminal encoding sequence and in the 3'-untranslated regions of PCMT transcripts generates three distinct classes of mRNAs which were cloned from testicular poly(A)+ RNA using 3'-RACE. Transcript splicing either 38 nt downstream or 7 nt upstream from the termination codon in exon 7 produces mRNAs encoding PCMT isozymes with -RWK or -RDEL, respectively, at their C-termini. The predominant transcript in testis, which is not detected in somatic tissues by Northern blotting and which may be specific to germ cells, is not spliced within exon 7 and also encodes the -RWK isozyme.

3T3 Cells↗
PubMed1996

Genomic structure and transcription of a murine odorant receptor gene: differential initiation of transcription in the olfactory and testicular cells.

We have characterized genomic structure and transcription of a murine odorant receptor (OR) gene, MOR23. This gene has two distinct transcriptional initiation regions, which are differentially utilized in the olfactory and testicular cells. We have found that the MOR23 gene has an intron within the 5'-untranslated region upstream of the coding sequence. In olfactory cells, transcription of the gene is initiated in the region upstream of this intron, while in testicular cells, transcription starts within the intron. Differential initiation of transcription is discussed in the context of tissue-specific expression of the OR genes.

Animals↗
PubMed1994

Transcriptional and post-transcriptional regulation of maternal and zygotic cytoskeletal tropomyosin mRNA during Drosophila development correlates with specific morphogenic events.

We have characterized maternal and zygotic cytoskeletal tropomyosin mRNA expression during Drosophila embryogenesis using in situ hybridization to endogenous cytoskeletal tropomyosin mRNA and a cytoskeletal tropomyosin promoter/beta-galactosidase-encoding fusion gene mRNA in transgenic flies. A 2.0-kb maternal cytoskeletal tropomyosin mRNA is synthesized in the nurse cells and transported into the oocyte during oogenesis. During early embryogenesis, this mRNA becomes localized to the pole cell region and then to the cortex during the cellular blastoderm stage. In later embryos it is localized to the ventral and cephalic furrows and extending germ band. The major zygotic mRNA is 2.4 kb and is first detected at gastrulation. In early embryos, this mRNA is expressed in the invaginating anterior and posterior midgut, the transverse furrows, and the amnioserosa, all regions of the embryo undergoing intense cellular movement, and in later embryos, predominantly in the gut, brain, and epidermis. A transgene construct containing 1.2 kb of 5' cytoskeletal tropomyosin promoter sequences driving expression of Escherichia coli beta-galactosidase and the cytoskeletal tropomyosin 3' untranslated region in transgenic flies has the same distribution of maternal and zygotic transcripts throughout oogenesis and embryonic development as the endogenous transcripts. A transgene containing the 3' untranslated region from either the hsp70 gene or the SV40 early genes, on the other hand, does not express maternal RNA. Furthermore, none of the transgenes expressed in the follicle cells, suggesting that expression in these cells is under different transcriptional control. Our results indicate that maternal and zygotic cytoskeletal tropomyosin mRNAs are localized to specific regions of the developing embryo, particularly in regions of the embryo undergoing cell movement and invagination. Furthermore, the synthesis, transport, and accumulation of this RNA is under transcriptional and post-transcriptional control.

Animals↗
PubMed1993

Coupling of rRNA transcription and ribosomal assembly in vivo. Formation of active ribosomal subunits in Escherichia coli requires transcription of rRNA genes by host RNA polymerase which cannot be replaced by bacteriophage T7 RNA polymerase.

Transcription of a plasmid-located rrnB operon and the corresponding formation of ribosomes in vivo were studied using either T7 RNA polymerase or host RNA polymerase as transcriptase. The 23 S rRNA gene on the plasmid carried an A1067-->T mutation, which confers resistance against the drug thiostrepton. The proportion of particles containing plasmid-borne 23 S rRNA versus chromosome-borne rRNA was quantified with a precision of better than 10% by scanning sequence autoradiograms around nucleotide 1067. The activity of these particles was determined in the presence of thiostrepton which exclusively abolishes the activity of chromosomal wild-type ribosomes. When the plasmid rrnB operon was transcribed with phage T7 RNA polymerase, up to 80% of the rRNA synthesis was plasmid-directed (pulse labelling) in the late induction phase, most of which (about 85%) became degraded. The cells accumulated 50 S particles with plasmid-borne intact rRNA that was hardly found in 70 S ribosomes, i.e. particles harbouring plasmid-borne rRNA did not enter the pool of active ribosomes. The particles with plasmid-derived rRNAs were also practically inactive in protein synthesis in vitro. However, the rRNA was functional as shown by reconstitution analysis. The same patterns were found at various expression levels of the plasmid rrnB operon, indicating that not the overproduction of rRNA but rather the T7 transcriptase was responsible for the observed effects. However, when the plasmid rrnB operon was transcribed with host RNA polymerase, growth was not affected upon induction, the 30 S to 50 S to 70 S ratios in the cell were not altered, both 50 S subunits and 70 S ribosomes contained large amounts of plasmid-borne rRNA, and the particles with plasmid-derived rRNA were active in vitro. When the induction of rRNA transcription by T7 RNA polymerase was performed at 25 degrees C instead of 37 degrees C, an almost normal pattern was observed. Inactive 50 S particles did not accumulate, and large amounts of plasmid-borne rRNA were found in the pool of 70 S ribosomes. Lowering the induction temperature reduces the transcription rate by T7 RNA polymerase, which is five times faster at 37 degrees C than the host polymerase. The results suggest that the formation of active ribosomal subunits in vivo requires a fine adaptation of the transcription rate of rRNAs and the assembly process, underlining the importance of a coupling between rRNA transcription and ribosome assembly in vivo. T7 RNA polymerase cannot replace the host RNA polymerase in this process at 37 degrees C.

Bacteriophage T7↗
PubMed2002

Aroclor 1254 modulates gene expression of nuclear transcription factors: implications for albumin gene transcription and protein synthesis in rat hepatocyte cultures.

Human exposure to polychlorinated biphenyls (PCBs) may lead to increased albumin serum levels, but little is known about the underlying events. Certain PCBs are also ligands for the aryl hydrocarbon receptor (Ahr) and this receptor regulates transcriptional activation of many different genes, including CYP1A1. We tested our hypothesis that expression of certain nuclear transcription factors is altered upon treatment of rat hepatocyte cultures with Aroclor 1254 and we studied the gene expression of albumin and liver-enriched transcription factors simultaneously. We correlate albumin gene expression with protein synthesis and we used CYP1A1 gene expression and enzyme activity as a surrogate endpoint for aryl hydrocarbon receptor activation. We found mRNA transcripts of CCAAT/enhancer binding protein alpha and gamma, hepatic nuclear factor 1, and hepatic nuclear factor 4 to be increased up to 62-fold, whereas albumin gene expression and secretion was increased 3-fold. Noticeably, expression of c-fos, c-jun (AP-1), HNF-6, CCAAT/enhancer binding protein beta and delta, tissue-specific enhancer-1, Ah-receptor, and albumin D-site-binding protein was unchanged. We show coordinate albumin gene expression and protein secretion in primary rat hepatocyte cultures and propose a relationship between induction of certain liver-enriched transcription factors and of the albumin gene via an Ahr-mediated mechanism.

Albumins↗
PubMed2000

Identification of a noncanonical signal for transcription of a novel subgenomic mRNA of mouse hepatitis virus: implication for the mechanism of coronavirus RNA transcription.

Subgenomic RNA transcription of coronaviruses involves the interaction between the leader (or antileader) and the intergenic (IG) sequences. However, it is not clear how these two sequences interact with each other. In this report, a previously unrecognized minor species of subgenomic mRNA, termed mRNA5-1, was identified in cells infected with mouse hepatitis virus (MHV) strains JHM2c, JHM(2), JHM(3), A59, and MHV-1. Sequence analysis revealed that the leader-body fusion site of the mRNA is located at approximately 150 nucleotides (nt) downstream of the consensus IG sequence for mRNA 5 and did not have sequence homology with any known IG consensus sequences. To determine whether this sequence functions independently as a promoter, we cloned a 140-nt sequence (from approximately 70 nt upstream to approximately 70 nt downstream of the fusion site) from viral genomic RNA and placed it in front of a reporter gene in the defective-interfering (DI) RNA-chloramphenicol acetyltransferase (CAT) reporter vector. Transfection of the reporter RNA into MHV-infected cells resulted in synthesis of a CAT-specific subgenomic mRNA detected by reverse transcription-polymerase chain reaction (RT-PCR). The strength of this promoter was similar to that of the IG7 (for mRNA 7) as measured by the CAT activity. Deletion analysis showed that the sequence as few as 13 nt was sufficient to initiate mRNA transcription, while mutations within the 13-nt abolished mRNA transcription. In vitro translation study confirmed that the envelope (E) protein was translated from mRNA5-1, which encodes the open reading frame (ORF) 5b at its 5'-end, indicating that mRNA5-1 is a functional message. Furthermore, when the ORF5b was replaced with the CAT gene and placed in the DI in the context of viral mini-genome, CAT was expressed not only from the first ORF of mRNA5-1 but also from the second and third ORF of mRNA5 and genomic DI RNA, respectively, suggesting that more than one mechanism is involved in regulation of ORF5b expression. Our findings thus support the notion that base-pairing between the leader (or antileader) and the IG is not the sole mechanism in subgenomic RNA transcription.

Animals↗