Showing papers on "Transcription factor published in 2000"
TL;DR: Analysis of genomic expression patterns in the yeast Saccharomyces cerevisiae implicated the transcription factors Yap1p, as well as Msn2p and Msn4p, in mediating specific features of the transcriptional response, while the identification of novel sequence elements provided clues to novel regulators.
Abstract: We explored genomic expression patterns in the yeast Saccharomyces cerevisiae responding to diverse environmental transitions. DNA microarrays were used to measure changes in transcript levels over time for almost every yeast gene, as cells responded to temperature shocks, hydrogen peroxide, the superoxide-generating drug menadione, the sulfhydryl-oxidizing agent diamide, the disulfide-reducing agent dithiothreitol, hyper- and hypo-osmotic shock, amino acid starvation, nitrogen source depletion, and progression into stationary phase. A large set of genes (approximately 900) showed a similar drastic response to almost all of these environmental changes. Additional features of the genomic responses were specialized for specific conditions. Promoter analysis and subsequent characterization of the responses of mutant strains implicated the transcription factors Yap1p, as well as Msn2p and Msn4p, in mediating specific features of the transcriptional response, while the identification of novel sequence elements provided clues to novel regulators. Physiological themes in the genomic responses to specific environmental stresses provided insights into the effects of those stresses on the cell.
4,836 citations
TL;DR: Recent progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1.
Abstract: NF-κB (nuclear factor-κB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-κ...
4,724 citations
TL;DR: T-bet initiates Th1 lineage development from naive Thp cells both by activating Th1 genetic programs and by repressing the opposing Th2 programs, as evidenced by the simultaneous induction of IFNgamma and repression of IL-4 and IL-5.
3,479 citations
TL;DR: It is shown that mouse Snail is a strong repressor of transcription of the E-cadherin gene, opening up new avenues for the design of specific anti-invasive drugs.
Abstract: The Snail family of transcription factors has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial-mesenchymal transitions) during embryonic development. Epithelial-mesenchymal transitions are also determinants of the progression of carcinomas, occurring concomitantly with the cellular acquisition of migratory properties following downregulation of expression of the adhesion protein E-cadherin. Here we show that mouse Snail is a strong repressor of transcription of the E-cadherin gene. Epithelial cells that ectopically express Snail adopt a fibroblastoid phenotype and acquire tumorigenic and invasive properties. Endogenous Snail protein is present in invasive mouse and human carcinoma cell lines and tumours in which E-cadherin expression has been lost. Therefore, the same molecules are used to trigger epithelial-mesenchymal transitions during embryonic development and in tumour progression. Snail may thus be considered as a marker for malignancy, opening up new avenues for the design of specific anti-invasive drugs.
3,426 citations
TL;DR: The completion of the Arabidopsis thaliana genome sequence allows a comparative analysis of transcriptional regulators across the three eukaryotic kingdoms and reveals the evolutionary generation of diversity in the regulation of transcription.
Abstract: The completion of the Arabidopsis thaliana genome sequence allows a comparative analysis of transcriptional regulators across the three eukaryotic kingdoms. Arabidopsis dedicates over 5% of its genome to code for more than 1500 transcription factors, about 45% of which are from families specific to plants. Arabidopsis transcription factors that belong to families common to all eukaryotes do not share significant similarity with those of the other kingdoms beyond the conserved DNA binding domains, many of which have been arranged in combinations specific to each lineage. The genome-wide comparison reveals the evolutionary generation of diversity in the regulation of transcription.
2,582 citations
TL;DR: This review focuses on the involvement of CBP/p300 in the complex biological processes that affect cell growth, transformation, and development.
Abstract: CREB binding protein (CBP) and p300 were both identified initially in protein interaction assays–the former through its association with the transcription factor CREB (Chrivia et al. 1993) and the latter through its interaction with the adenoviral-transforming protein E1A (Stein et al. 1990; Eckner et al. 1994). The recognition that these two proteins, one involved in transcription and the other in cell transformation, had highly conserved sequences suggested that they had the potential to participate in a variety of cellular functions (Fig. 1). Several excellent reviews (Janknecht and Hunter 1996; Shikama et al. 1997; Giles et al. 1998) have addressed the transcriptional coactivator functions of CBP/p300; this review focuses on the involvement of these proteins in the complex biological processes that affect cell growth, transformation, and development.
1,691 citations
TL;DR: It is shown that Nrf2 controls the expression of a group of electrophile- and oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system xc −) activity.
1,367 citations
TL;DR: A novel approach for enhancing the accumulation of natural products based on activation tagging by Agrobacterium-mediated transformation with a T-DNA that carries cauliflower mosaic virus 35S enhancer sequences at its right border is reported.
Abstract: Plants produce a wide array of natural products, many of which are likely to be useful bioactive structures. Unfortunately, these complex natural products usually occur at very low abundance and with restricted tissue distribution, thereby hindering their evaluation. Here, we report a novel approach for enhancing the accumulation of natural products based on activation tagging by Agrobacterium-mediated transformation with a T-DNA that carries cauliflower mosaic virus 35S enhancer sequences at its right border. Among ∼5000 Arabidopsis activation-tagged lines, we found a plant that exhibited intense purple pigmentation in many vegetative organs throughout development. This upregulation of pigmentation reflected a dominant mutation that resulted in massive activation of phenylpropanoid biosynthetic genes and enhanced accumulation of lignin, hydroxycinnamic acid esters, and flavonoids, including various anthocyanins that were responsible for the purple color. These phenotypes, caused by insertion of the viral enhancer sequences adjacent to an MYB transcription factor gene, indicate that activation tagging can overcome the stringent genetic controls regulating the accumulation of specific natural products during plant development. Our findings suggest a functional genomics approach to the biotechnological evaluation of phytochemical biodiversity through the generation of massively enriched tissue sources for drug screening and for isolating underlying regulatory and biosynthetic genes.
1,345 citations
TL;DR: It is shown that disruption of the murine GSK-3β gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumour necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor activation NF-κB.
Abstract: Glycogen synthase kinase-3 (GSK-3)-α and -β are closely related protein-serine kinases, which act as inhibitory components of Wnt signalling during embryonic development and cell proliferation in adult tissues1,2. Insight into the physiological function of GSK-3 has emerged from genetic analysis in Drosophila3,4, Dictyostelium 5 and yeast6,7. Here we show that disruption of the murine GSK-3β gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumour necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor activation NF-κB. GSK-3β-deficient embryos were rescued by inhibition of TNF using an anti-TNF-α antibody. Fibroblasts from GSK-3β-deficient embryos were hypersensitive to TNF-α and showed reduced NF-κB function. Lithium treatment (which inhibits GSK-3; refs 8, 9) sensitized wild-type fibroblasts to TNF and inhibited transactivation of NF-κB. The early steps leading to NF-κB activation (degradation of I-κB and translocation of NF-κB to the nucleus) were unaffected by the loss of GSK-3β, indicating that NF-κB is regulated by GSK-3β at the level of the transcriptional complex. Thus, GSK-3β facilitates NF-κB function.
1,335 citations
TL;DR: The Myc/Max/Mad network comprises a group of transcription factors whose distinct interactions result in gene-specific transcriptional activation or repression and can be viewed as a functional module which acts to convert environmental signals into specific gene-regulatory programs.
Abstract: The Myc/Max/Mad network comprises a group of transcription factors whose distinct interactions result in gene-specific transcriptional activation or repression. A great deal of research indicates that the functions of the network play roles in cell proliferation, differentiation, and death. In this review we focus on the Myc and Mad protein families and attempt to relate their biological functions to their transcriptional activities and gene targets. Both Myc and Mad, as well as the more recently described Mnt and Mga proteins, form heterodimers with Max, permitting binding to specific DNA sequences. These DNA-bound heterodimers recruit coactivator or corepressor complexes that generate alterations in chromatin structure, which in turn modulate transcription. Initial identification of target genes suggests that the network regulates genes involved in the cell cycle, growth, life span, and morphology. Because Myc and Mad proteins are expressed in response to diverse signaling pathways, the network can be viewed as a functional module which acts to convert environmental signals into specific gene-regulatory programs.
1,288 citations
TL;DR: It is suggested that both AREB1 and AREB2 function as transcriptional activators in the ABA-inducible expression of rd29B, and further that A BA-dependent posttranscriptional activation of AREB 1 and AREb2, probably by phosphorylation, is necessary for their maximum activation by ABA.
Abstract: The induction of the dehydration-responsive Arabidopsis gene, rd29B, is mediated mainly by abscisic acid (ABA). Promoter analysis of rd29B indicated that two ABA-responsive elements (ABREs) are required for the dehydration-responsive expression of rd29B as cis-acting elements. Three cDNAs encoding basic leucine zipper (bZIP)-type ABRE-binding proteins were isolated by using the yeast one-hybrid system and were designated AREB1, AREB2, and AREB3 (ABA-responsive element binding protein). Transcription of the AREB1 and AREB2 genes is up-regulated by drought, NaCl, and ABA treatment in vegetative tissues. In a transient transactivation experiment using Arabidopsis leaf protoplasts, both the AREB1 and AREB2 proteins activated transcription of a reporter gene driven by ABRE. AREB1 and AREB2 required ABA for their activation, because their transactivation activities were repressed in aba2 and abi1 mutants and enhanced in an era1 mutant. Activation of AREBs by ABA was suppressed by protein kinase inhibitors. These results suggest that both AREB1 and AREB2 function as transcriptional activators in the ABA-inducible expression of rd29B, and further that ABA-dependent posttranscriptional activation of AREB1 and AREB2, probably by phosphorylation, is necessary for their maximum activation by ABA. Using cultured Arabidopsis cells, we demonstrated that a specific ABA-activated protein kinase of 42-kDa phosphorylated conserved N-terminal regions in the AREB proteins.
Journal Article•
TL;DR: A new class of HIF-1-responsive gene is defined, the activation of which has implications for the understanding of hypoxic tumor metabolism and which may provide endogenous markers for tumor hypoxia.
Abstract: The transcriptional complex hypoxia-inducible factor-1 (HIF-1) has emerged as an important mediator of gene expression patterns in tumors, although the range of responding genes is still incompletely defined. Here we show that the tumor-associated carbonic anhydrases (CAs) are tightly regulated by this system. Both CA9 and CA12 were strongly induced by hypoxia in a range of tumor cell lines. In renal carcinoma cells that are defective for the von Hippel-Lindau (VHL) tumor suppressor, up-regulation of these CAs is associated with loss of regulation by hypoxia, consistent with the critical function of pVHL in the regulation of HIF-1. Further studies of CA9 defined a HIF-1-dependent hypoxia response element in the minimal promoter and demonstrated that tight regulation by the HIF/pVHL system was reflected in the pattern of CA IX expression within tumors. Generalized up-regulation of CA IX in VHL-associated renal cell carcinoma contrasted with focal perinecrotic expression in a variety of non-VHL-associated tumors. In comparison with vascular endothelial growth factor mRNA, expression of CA IX demonstrated a similar, although more tightly circumscribed, pattern of expression around regions of necrosis and showed substantial although incomplete overlap with activation of the hypoxia marker pimonidazole. These studies define a new class of HIF-1-responsive gene, the activation of which has implications for the understanding of hypoxic tumor metabolism and which may provide endogenous markers for tumor hypoxia.
TL;DR: In the majority of solid tumors examined, including bladder, brain, breast, colon, ovarian, pancreatic, prostate, and renal carcinomas, nuclear expression of HIF-1α and -2α was observed in varying subsets of the tumor cells.
Abstract: The cellular response to hypoxia includes the hypoxia-inducible factor-1 (HIF-1)-induced transcription of genes involved in diverse processes such as glycolysis and angiogenesis. Induction of the HIF-regulated genes, as a consequence of the microenvironment or genetic changes, is known to have an important role in the growth of experimental tumors. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) are known to dimerize with the aryl hydrocarbon receptor nuclear translocator in mediating this response. Because regulation of the α chain protein level is a primary determinant of HIF activity, our aim was to investigate the distribution of HIF-1α and HIF-2α by immunohistochemistry in normal and pathological tissues using monoclonal antibodies (mAb). We raised a new mAb to detect HIF-1α, designated 122, and used our previously validated mAb 190b to HIF-2α. In the majority of solid tumors examined, including bladder, brain, breast, colon, ovarian, pancreatic, prostate, and renal carcinomas, nuclear expression of HIF-1α and -2α was observed in varying subsets of the tumor cells. HIF-2α was also strongly expressed by subsets of tumor-associated macrophages, sometimes in the absence of any tumor cell expression. Less frequently staining was observed in other stromal cells within the tumors and in normal tissue adjacent to tumor margins. In contrast, in normal tissue neither molecule was detectable except within subsets of bone marrow macrophages, where HIF-2α was strongly expressed.
TL;DR: The importance of STAT activation to growth control in experiments using anti-sense molecules or dominant negative STAT protein encoding constructs performed in cell lines or studies in animals lacking specific STATs strongly indicate that STATs play an important role in controlling cell cycle progression and apoptosis.
Abstract: The STAT proteins (Signal Transducers and Activators of Transcription), were identified in the last decade as transcription factors which were critical in mediating virtually all cytokine driven signaling. These proteins are latent in the cytoplasm and become activated through tyrosine phosphorylation which typically occurs through cytokine receptor associated kinases (JAKs) or growth factor receptor tyrosine kinases. Recently a number of non-receptor tyrosine kinases (for example src and abl) have been found to cause STAT phosphorylation. Phosphorylated STATs form homo- or hetero-dimers, enter the nucleus and working coordinately with other transcriptional co-activators or transcription factors lead to increased transcriptional initiation. In normal cells and in animals, ligand dependent activation of the STATs is a transient process, lasting for several minutes to several hours. In contrast, in many cancerous cell lines and tumors, where growth factor dysregulation is frequently at the heart of cellular transformation, the STAT proteins (in particular Stats 1, 3 and 5) are persistently tyrosine phosphorylated or activated. The importance of STAT activation to growth control in experiments using anti-sense molecules or dominant negative STAT protein encoding constructs performed in cell lines or studies in animals lacking specific STATs strongly indicate that STATs play an important role in controlling cell cycle progression and apoptosis. Stat1 plays an important role in growth arrest, in promoting apoptosis and is implicated as a tumor suppressor; while Stats 3 and 5 are involved in promoting cell cycle progression and cellular transformation and preventing apoptosis. Many questions remain including: (1) a better understanding of how the STAT proteins through association with other factors increase transcription initiation; (2) a more complete definition of the sets of genes which are activated by different STATs and (3) how these sets of activated genes differ as a function of cell type. Finally, in the context of many cancers, where STATs are frequently persistently activated, an understanding of the mechanisms leading to their constitutive activation and defining the potential importance of persistent STAT activation in human tumorigenesis remains. Oncogene (2000).
TL;DR: PGC-1 is identified as a coactivator of PPAR α in the transcriptional control of mitochondrial FAO capacity, separable PPARα interaction and transactivation domains within the PGC-1 molecule are defined, and it is demonstrated that certain features of the PPARβ–PGC1 interaction are distinct from that of PP ARγ-1.
Abstract: Peroxisome proliferator-activated receptor α (PPARα) plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid β-oxidation (FAO) enzymes. In this study we sought to determine whether the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of coactivating PPARα in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demonstrated that PGC-1 enhanced PPARα-mediated transcriptional activation of reporter plasmids containing PPARα target elements. PGC-1 also enhanced the transactivation activity of a PPARα-Gal4 DNA binding domain fusion protein. Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPARα and PGC-1 cooperatively induced the expression of PPARα target genes and increased cellular palmitate oxidation rates. Glutathione S-transferase “pulldown” studies revealed that in contrast to the previously reported ligand-independent interaction with PPARγ, PGC-1 binds PPARα in a ligand-influenced manner. Protein-protein interaction studies and mammalian cell hybrid experiments demonstrated that the PGC-1–PPARα interaction involves an LXXLL domain in PGC-1 and the PPARα AF2 region, consistent with the observed ligand influence. Last, the PGC-1 transactivation domain was mapped to within the NH2-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPARα interacting domains. These results identify PGC-1 as a coactivator of PPARα in the transcriptional control of mitochondrial FAO capacity, define separable PPARα interaction and transactivation domains within the PGC-1 molecule, and demonstrate that certain features of the PPARα–PGC-1 interaction are distinct from that of PPARγ–PGC-1.
TL;DR: The winged helix/forkhead class of transcription factors is characterized by a 100-amino-acid, monomeric DNAbinding domain, which folds into a variant of the helix–turn–helix motif and is made up of three a helices and two characteristic large loops, or “wings.”
Abstract: The winged helix/forkhead class of transcription factors is characterized by a 100-amino-acid, monomeric DNAbinding domain. The structure of the DNA-binding domain of one of the class members, hepatocyte nuclear factor 3 g (HNF3g), in a complex with a DNA target has been solved (Clark et al. 1993). The DNA-binding domain folds into a variant of the helix–turn–helix motif and is made up of three a helices and two characteristic large loops, or “wings.” Therefore, the DNA-binding motif has been named the winged helix DNA-binding domain. Over the past 9 years since the identification of the first member of this class, the Drosophila melanogaster gene Fork head, >100 members of this gene family have been identified (for review, see Kaufmann and Knöchel 1996) in species ranging from yeast to human. The rapid accumulation of sequences by many different laboratories has led to the use of multiple names and classification systems, making it very difficult to follow the literature and to name newly characterized winged helix/ forkhead transcription factors. This problem was recognized and discussed at the first International Meeting on Forkhead/Winged Helix Proteins, held in La Jolla, California, in November 1998. At that time a proposal was developed to standardize the nomenclature for these proteins. Fox (Forkhead box) was adopted as the unified symbol for all chordate winged helix/forkhead transcription factors. A winged helix/forkhead nomenclature committee was elected to implement this proposal, in consultation with the community at large. This final proposal has been endorsed by >20 scientists as well as the Human and Mouse Gene Nomenclature Committees.
TL;DR: Comparison of seed and ABA-inducible vegetative gene expression in wild-type and abi5-1 plants indicates that ABI5 regulates a subset of late embryogenesis–abundant genes during both developmental stages.
Abstract: The Arabidopsis abscisic acid (ABA)-insensitive abi5 mutants have pleiotropic defects in ABA response, including decreased sensitivity to ABA inhibition of germination and altered expression of some ABA-regulated genes. We isolated the ABI5 gene by using a positional cloning approach and found that it encodes a member of the basic leucine zipper transcription factor family. The previously characterized abi5-1 allele encodes a protein that lacks the DNA binding and dimerization domains required for ABI5 function. Analyses of ABI5 expression provide evidence for ABA regulation, cross-regulation by other ABI genes, and possibly autoregulation. Comparison of seed and ABA-inducible vegetative gene expression in wild-type and abi5-1 plants indicates that ABI5 regulates a subset of late embryogenesis-abundant genes during both developmental stages.
TL;DR: AtERFs are factors that respond to extracellular signals to modulate GCC box–mediated gene expression positively or negatively, and are concluded that AtERF genes were differentially regulated by ethylene and by abiotic stress conditions.
Abstract: Ethylene-responsive element binding factors (ERFs) are members of a novel family of transcription factors that are specific to plants. A highly conserved DNA binding domain known as the ERF domain is the unique feature of this protein family. To characterize in detail this family of transcription factors, we isolated Arabidopsis cDNAs encoding five different ERF proteins (AtERF1 to AtERF5) and analyzed their structure, DNA binding preference, transactivation ability, and mRNA expression profiles. The isolated AtERFs were placed into three classes based on amino acid identity within the ERF domain, although all five displayed GCC box–specific binding activity. AtERF1, AtERF2, and AtERF5 functioned as activators of GCC box–dependent transcription in Arabidopsis leaves. By contrast, AtERF3 and AtERF4 acted as repressors that downregulated not only basal transcription levels of a reporter gene but also the transactivation activity of other transcription factors. The AtERF genes were differentially regulated by ethylene and by abiotic stress conditions, such as wounding, cold, high salinity, or drought, via ETHYLENE-INSENSITIVE2 (EIN2)–dependent or –independent pathways. Cycloheximide, a protein synthesis inhibitor, also induced marked accumulation of AtERF mRNAs. Thus, we conclude that AtERFs are factors that respond to extracellular signals to modulate GCC box–mediated gene expression positively or negatively.
TL;DR: It is shown that extracts from VHL-deficient renal carcinoma cells have a defect in HIF-α ubiquitylation activity which is complemented by exogenous pVHL, and this defect was specific for Hif-α among a range of substrates tested.
TL;DR: It is reported here that 15d-PGJ(2) potently inhibits NF-kappaB-dependent transcription by two additional PPARgamma-independent mechanisms that act in combination to inhibit transactivation of the NF- kappaB target gene cyclooxygenase 2.
Abstract: Prostaglandin J2 (PGJ2) and its metabolites Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) are naturally occurring derivatives of prostaglandin D2 that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ2 is a high-affinity ligand for the peroxisome proliferator-activated receptor γ (PPARγ) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor α, in a PPARγ-dependent manner. We report here that 15d-PGJ2 potently inhibits NF-κB-dependent transcription by two additional PPARγ-independent mechanisms. Several lines of evidence suggest that 15d-PGJ2 directly inhibits NF-κB-dependent gene expression through covalent modifications of critical cysteine residues in IκB kinase and the DNA-binding domains of NF-κB subunits. These mechanisms act in combination to inhibit transactivation of the NF-κB target gene cyclooxygenase 2. Direct inhibition of NF-κB signaling by 15d-PGJ2 may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs.
TL;DR: It is reported that withdrawal of cytokine results in upregulation of Bimexpression concomitant with induction of the apoptotic program in lymphocytes, and a mechanism by which cytokines promote lymphocyte survival by inhibition of FKHR-L1, preventing Bim expression is proposed.
TL;DR: The chapter describes a three-step model of pS3 activation by stress signals and concludes with the potential clinical applications of the detection of p53 mutations in human tissues.
Abstract: Publisher Summary The p53 protein is a tight, hydrophobic central globule containing the DNA binding domain, flanked by accessible N- and C-terminal regions This protein is expressed in all cell types but has a rapid turnover and is latent under normal conditions p53 is mutated in most common human malignancies and behaves as a multifunctional transcription factor involved in the control of cell cycle, programmed cell death, senescence, differentiation and development, transcription, DNA replication, DNA repair, and maintenance of genomic stability p53 is converted to an active form in response to a number of physical or chemical DNA-damaging agents such as X or gamma irradiation, UV rays, oxidizing agents, cytotoxic drugs, and cancer-causing chemicals Induction of p53 implies nuclear retention, accumulation of the protein as a result of post-translational stabilization, and allosteric conversion to a form with high sequence-specific DNA-binding capacity p53 is activated in response to DNA damage, thus acting as a “guardian of the genome” against genotoxic stress The chapter describes a three-step model of pS3 activation by stress signals The downstream pS3 signaling is mediated by transcriptional activation of specific genes and by complex formation between p53 and heterologous proteins The mutations and variations in the p53 gene are due to p53 polymorphisms, somatic mutations, and germline mutations in p53 The chapter also accounts for p53 mutations in sporadic cancers focussing on host-environment interactions The chapter concludes with the potential clinical applications of the detection of p53 mutations in human tissues
TL;DR: The results indicate that cellular cholesterol efflux is controlled, at least in part, at the level of transcription by a nuclear receptor-signaling pathway, and suggest a model in which activation of LXRs by oxysterols in response to cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux to extracellular acceptors.
Abstract: LXRα is a nuclear receptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids. Here we define a role for this transcription factor in the control of cellular cholesterol efflux. We demonstrate that retroviral expression of LXRα in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of these cells with oxysterol ligands of LXR results in 7- to 30-fold induction of the mRNA encoding the putative cholesterol/phospholipid transporter ATP-binding cassette (ABC)A1. In contrast, induction of ABCA1 mRNA in response to oxysterols is attenuated in cells that constitutively express dominant-negative forms of LXRα or LXRβ that lack the AF2 transcriptional activation domain. We further demonstrate that expression of LXRα in NIH 3T3 fibroblasts and/or treatment of these cells with oxysterols is sufficient to stimulate cholesterol efflux to extracellular apolipoprotein AI. The ability of oxysterol ligands of LXR to stimulate efflux is dramatically reduced in Tangier fibroblasts, which carry a loss of function mutation in the ABCA1 gene. Taken together, these results indicate that cellular cholesterol efflux is controlled, at least in part, at the level of transcription by a nuclear receptor–signaling pathway. They suggest a model in which activation of LXRs by oxysterols in response to cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux to extracellular acceptors. These findings have important implications for our understanding of mammalian cholesterol homeostasis and suggest new opportunities for pharmacological regulation of cellular lipid metabolism.
TL;DR: It is concluded that specific and direct interactions between ATF6 and ERSE are critical for transcriptional induction not only of ER chaperones but also of CHOP and XBP-1.
Abstract: Transcription of genes encoding molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) is induced by accumulation of unfolded proteins in the ER. This intracellular signaling, known as the unfolded protein response (UPR), is mediated by the cis-acting ER stress response element (ERSE) in mammals. In addition to ER chaperones, the mammalian transcription factor CHOP (also called GADD153) is induced by ER stress. We report here that the transcription factor XBP-1 (also called TREB5) is also induced by ER stress and that induction of CHOP and XBP-1 is mediated by ERSE. The ERSE consensus sequence is CCAAT-N9-CCACG. As the general transcription factor NF-Y (also known as CBF) binds to CCAAT, CCACG is considered to provide specificity in the mammalian UPR. We recently found that the basic leucine zipper protein ATF6 isolated as a CCACG-binding protein is synthesized as a transmembrane protein in the ER, and ER stress-induced proteolysis produces a soluble form of ATF6 that translocates into the nucleus. We report here that overexpression of soluble ATF6 activates transcription of the CHOP and XBP-1 genes as well as of ER chaperone genes constitutively, whereas overexpression of a dominant negative mutant of ATF6 blocks the induction by ER stress. Furthermore, we demonstrated that soluble ATF6 binds directly to CCACG only when CCAAT exactly 9 bp upstream of CCACG is bound to NF-Y. Based on these and other findings, we concluded that specific and direct interactions between ATF6 and ERSE are critical for transcriptional induction not only of ER chaperones but also of CHOP and XBP-1.
TL;DR: This work proposes that selective estrogen receptor modulator (SERM) complexes with ERbeta and with truncated ERalpha derivatives use their DNA binding domain to titrate histone deacetylase (HDAC)-repressor complexes away from the Jun/Fos coactivator complex, thereby allowing unfettered activity of the coactivators.
TL;DR: The role of NF-kappaB in cytokine-induced muscle degeneration was explored and its expression was down-regulated by TNF and IFN-gamma expression in mouse muscle in vivo, elucidate a possible mechanism that may underlie the skeletal muscle decay in cachexia.
Abstract: MyoD regulates skeletal muscle differentiation (SMD) and is essential for repair of damaged tissue. The transcription factor nuclear factor kappa B (NF-kappaB) is activated by the cytokine tumor necrosis factor (TNF), a mediator of skeletal muscle wasting in cachexia. Here, the role of NF-kappaB in cytokine-induced muscle degeneration was explored. In differentiating C2C12 myocytes, TNF-induced activation of NF-kappaB inhibited SMD by suppressing MyoD mRNA at the posttranscriptional level. In contrast, in differentiated myotubes, TNF plus interferon-gamma (IFN-gamma) signaling was required for NF-kappaB-dependent down-regulation of MyoD and dysfunction of skeletal myofibers. MyoD mRNA was also down-regulated by TNF and IFN-gamma expression in mouse muscle in vivo. These data elucidate a possible mechanism that may underlie the skeletal muscle decay in cachexia.
TL;DR: There is strong biochemical and genetic evidence that the IKK complex, which consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, Ikkγ, is the master regulator of NF-κB-mediated innate immune and inflammatory responses.
TL;DR: Orca3 overexpression resulted in enhanced expression of several metabolite biosynthetic genes and in increased accumulation of terpenoid indole alkaloids, which may link plant stress responses to changes in metabolism.
Abstract: Biosynthesis of many classes of secondary metabolites in plants is induced by the stress hormone jasmonate. The gene for ORCA3, a jasmonate-responsive APETALA2 (AP2)-domain transcription factor from Catharanthus roseus, was isolated by transferred DNA activation tagging. Orca3 overexpression resulted in enhanced expression of several metabolite biosynthetic genes and, consequently, in increased accumulation of terpenoid indole alkaloids. Regulation of metabolite biosynthetic genes by jasmonate-responsive AP2-domain transcription factors may link plant stress responses to changes in metabolism.
TL;DR: It is proposed that loss of PTEN during malignant progression contributes to tumor expansion through the deregulation of Akt activity and HIF-1-regulated gene expression.
Abstract: In glioblastoma-derived cell lines, PTEN does not significantly alter apoptotic sensitivity or cause complete inhibition of DNA synthesis. However, in these cell lines PTEN regulates hypoxia- and IGF-1-induced angiogenic gene expression by regulating Akt activation of HIF-1 activity. Restoration of wild-type PTEN to glioblastoma cell lines lacking functional PTEN ablates hypoxia and IGF-1 induction of HIF-1-regulated genes. In addition, Akt activation leads to HIF-1alpha stabilization, whereas PTEN attenuates hypoxia-mediated HIF-1alpha stabilization. We propose that loss of PTEN during malignant progression contributes to tumor expansion through the deregulation of Akt activity and HIF-1-regulated gene expression.
TL;DR: The results show that deacetylation and functional interactions by the PID/MTA2-associated NuRD complex may represent an important pathway to regulate p53 function.
Abstract: The p53 tumour suppressor is a transcriptional factor whose activity is modulated by protein stability and post-translational modifications including acetylation. The mechanism by which acetylated p53 is maintained in vivo remains unclear. Here we show that the deacetylation of p53 is mediated by an histone deacetylase-1 (HDAC1)-containing complex. We have also purified a p53 target protein in the deacetylase complexes (designated PID; but identical to metastasis-associated protein 2 (MTA2)), which has been identified as a component of the NuRD complex. PID specifically interacts with p53 both in vitro and in vivo, and its expression reduces significantly the steady-state levels of acetylated p53. PID expression strongly represses p53-dependent transcriptional activation, and, notably, it modulates p53-mediated cell growth arrest and apoptosis. These results show that deacetylation and functional interactions by the PID/MTA2-associated NuRD complex may represent an important pathway to regulate p53 function.