Showing papers on "Transcription factor published in 2009"
TL;DR: Much progress has been made in the past two years revealing new insights into the regulation and functions of NF-kappaB, and this recent progress is covered in this review.
Abstract: The mammalian Rel/NF-κB family of transcription factors, including RelA, c-Rel, RelB, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation. The five members of the NF-κB family are normally kept inactive in the cytoplasm by interaction with inhibitors called IκBs or the unprocessed forms of NF-κB1 and NF-κB2. A wide variety of signals emanating from antigen receptors, pattern-recognition receptors, receptors for the members of TNF and IL-1 cytokine families, and others induce differential activation of NF-κB heterodimers. Although work over the past two decades has shed significant light on the regulation of NF-κB transcription factors and their functions, much progress has been made in the past two years revealing new insights into the regulation and functions of NF-κB...
2,380 citations
TL;DR: The NF-kappaB pathway is a paradigm for understanding general principles of signal transduction and gene regulation as well as other pathway-specific mediators, and the transcription factors are themselves extensively modified.
Abstract: Nuclear factor-κB (NF-κB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival. Inducible NF-κB activation depends on phosphorylation-induced proteosomal degradation of the inhibitor of NF-κB proteins (IκBs), which retain inactive NF-κB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-κB activation converge on the IκB kinase (IKK) complex, which is responsible for IκB phosphorylation and is essential for signal transduction to NF-κB. Additional regulation of NF-κB activity is achieved through various post-translational modifications of the core components of the NF-κB signaling pathways. In addition to cytosolic modifications of IKK and IκB proteins, as well as other pathway-specific mediators, the transcription factors are themselves extensively modified. Tremendous progress has been made over the last two decades in unraveling the elaborate regulatory networks that control the NF-κB response. This has made the NF-κB pathway a paradigm for understanding general principles of signal transduction and gene regulation.
2,093 citations
TL;DR: An analysis of 1,391 manually curated sequence-specific DNA-binding transcription factors, their functions, genomic organization and evolutionary conservation provides a solid foundation for future investigations to elucidate regulatory mechanisms underlying diverse mammalian biological processes.
Abstract: Transcription factors are key cellular components that control gene expression: their activities determine how cells function and respond to the environment. Currently, there is great interest in research into human transcriptional regulation. However, surprisingly little is known about these regulators themselves. For example, how many transcription factors does the human genome contain? How are they expressed in different tissues? Are they evolutionarily conserved? Here, we present an analysis of 1,391 manually curated sequence-specific DNA-binding transcription factors, their functions, genomic organization and evolutionary conservation. Much remains to be explored, but this study provides a solid foundation for future investigations to elucidate regulatory mechanisms underlying diverse mammalian biological processes.
1,489 citations
TL;DR: The transition from the juvenile to the adult phase of shoot development in plants is accompanied by changes in vegetative morphology and an increase in reproductive potential, and the regulatory mechanism is described, which is mediated by sequentially operating miRNAs.
1,344 citations
TL;DR: The switching on and off of Nrf2 protects cells against free radical damage, prevents apoptosis, and promotes cell survival, and is a mechanism of critical importance for cellular protection and cell survival.
1,336 citations
TL;DR: In a subset of CD4+ T cells, the activities of the transcription factors Foxp3 and T-bet are overlaid, which results in Treg cells with unique homeostatic and migratory properties optimized for the suppression of TH1 responses in vivo.
Abstract: Several subsets of Foxp3+ regulatory T cells are known to exist. Campbell and colleagues show that one subset of regulatory T cells requires the transcription factor T-bet during T helper type 1–mediated immune responses in vivo. Several subsets of Foxp3+ regulatory T cells (Treg cells) work in concert to maintain immune homeostasis. However, the molecular bases underlying the phenotypic and functional diversity of Treg cells remain obscure. We show that in response to interferon-γ, Foxp3+ Treg cells upregulated the T helper type 1 (TH1)-specifying transcription factor T-bet. T-bet promoted expression of the chemokine receptor CXCR3 on Treg cells, and T-bet+ Treg cells accumulated at sites of TH1 cell–mediated inflammation. Furthermore, T-bet expression was required for the homeostasis and function of Treg cells during type 1 inflammation. Thus, in a subset of CD4+ T cells, the activities of the transcription factors Foxp3 and T-bet are overlaid, which results in Treg cells with unique homeostatic and migratory properties optimized for the suppression of TH1 responses in vivo.
1,129 citations
TL;DR: Overall, the studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.
1,120 citations
TL;DR: It is shown that interleukin-1 (IL-1) signaling on T cells is critically required for the early programming of Th 17 cell lineage and Th17 cell-mediated autoimmunity and this pathway may serve as a unique target for Th17cell-mediated immunopathology.
1,102 citations
TL;DR: IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.
Abstract: Heterozygous mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. We have shown that tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, alpha-ketoglutarate (alpha-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF-1alpha levels was reversible by an alpha-KG derivative. HIF-1alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.
1,078 citations
TL;DR: An emerging area of research unravels additional activities of p53 in the cytoplasm, where it triggers apoptosis and inhibits autophagy, which contribute to the mission of p 53 as a tumour suppressor.
Abstract: The principal tumour-suppressor protein, p53, accumulates in cells in response to DNA damage, oncogene activation and other stresses. It acts as a nuclear transcription factor that transactivates genes involved in apoptosis, cell cycle regulation and numerous other processes. An emerging area of research unravels additional activities of p53 in the cytoplasm, where it triggers apoptosis and inhibits autophagy. These previously unknown functions contribute to the mission of p53 as a tumour suppressor.
1,020 citations
TL;DR: Findings show that the modulation of p62 by autophagy is a key factor in tumorigenesis, and place p62 at critical decision points that control cell death and survival.
TL;DR: A broad survey of transcription factors reveals that related proteins can have multiple and differing DNA binding specificities, which may be important in gene regulation and in the evolution of transcriptional regulatory networks.
Abstract: Sequence preferences of DNA binding proteins are a primary mechanism by which cells interpret the genome. Despite the central importance of these proteins in physiology, development, and evolution, comprehensive DNA binding specificities have been determined experimentally for only a few proteins. Here, we used microarrays containing all 10-base pair sequences to examine the binding specificities of 104 distinct mouse DNA binding proteins representing 22 structural classes. Our results reveal a complex landscape of binding, with virtually every protein analyzed possessing unique preferences. Roughly half of the proteins each recognized multiple distinctly different sequence motifs, challenging our molecular understanding of how proteins interact with their DNA binding sites. This complexity in DNA recognition may be important in gene regulation and in the evolution of transcriptional regulatory networks.
TL;DR: The mechanisms of and the emerging principles in the transcriptional regulation of inflammatory responses in diverse physiological settings are discussed.
Abstract: Inflammation is a multicomponent response to tissue stress, injury and infection, and a crucial point of its control is at the level of gene transcription. The inducible inflammatory gene expression programme--such as that triggered by Toll-like receptor signalling in macrophages--is comprised of several coordinately regulated sets of genes that encode key functional programmes; these are controlled by three classes of transcription factors, as well as various transcriptional co-regulators and chromatin modifications. Here, we discuss the mechanisms of and the emerging principles in the transcriptional regulation of inflammatory responses in diverse physiological settings.
TL;DR: The findings suggest that Tregs adapt to their environment by engaging distinct effector response–specific suppression modalities upon activation of STAT proteins that direct the corresponding class of the immune response.
Abstract: Immune responses are kept in check by Foxp3-expressing CD4+-regulatory T cells (Tregs) through a variety of mechanisms. Expression of specific transcription factors directs Treg responses into distinct T helper cell lineages; however, the transcription factors that regulate particular helper lineages have not been completely characterized. Chaudhry et al. (p. [986][1], published online 1 October) show that the transcription factor Stat3, that is required for the initial differentiation of TH17-effector T cells, is also required for Treg cell-mediated suppression of TH17-mediated immune responses. Mice carrying a Treg cellspecific deletion in Stat3 succumb to an intestinal inflammatory disease driven by uncontrolled TH17 responses. Thus, different classes of immune responses can result from the expression of helper lineage–specific transcription factors.
[1]: /lookup/doi/10.1126/science.1172702
TL;DR: The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation.
Abstract: Transcription is a molecular requisite for long-term synaptic plasticity and long-term memory formation. Thus, in the last several years, one main interest of molecular neuroscience has been the identification of families of transcription factors that are involved in both of these processes. Transcription is a highly regulated process that involves the combined interaction and function of chromatin and many other proteins, some of which are essential for the basal process of transcription, while others control the selective activation or repression of specific genes. These regulated interactions ultimately allow a sophisticated response to multiple environmental conditions, as well as control of spatial and temporal differences in gene expression. Evidence based on correlative changes in expression, genetic mutations, and targeted molecular inhibition of gene expression have shed light on the function of transcription in both synaptic plasticity and memory formation. This review provides a brief overview ...
TL;DR: Data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.
Abstract: Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the liver and heart. In Stat3(-/-) cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.
TL;DR: It is proposed that active Tead4 promotes TE development in outside cells, whereas Tead 4 activity is suppressed in inside cells by cell contact- and Lats-mediated inhibition of nuclear Yap localization, and differential signaling between inside and outside cell populations leads to changes in cell fate specification during TE formation.
Journal Article•
TL;DR: The c-Myc oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miB-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells, which leads to upregulation of glutamine catabolism.
Abstract: Notwithstanding the renewed interest in the Warburg effect, which describes the propensity for cancer cells to avidly metabolize glucose to lactate, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine is a major source for energy, carbon and nitrogen for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood. Here, we report that the c-Myc oncogenic transcription factor regulates glutamine metabolism by a previously unsuspected mechanism which involves c-Myc suppression of miR-23 microRNAs that target and inhibit mitochondrial glutaminase, or GLS, the first enzyme that catabolizes glutamine. c-Myc also transactivates expression of glutamine transporter genes. We studied the human P-493 B cells that bear a tetracycline-repressible c-Myc construct, such that tetracycline withdrawal induces c-Myc and mitochondrial biogenesis followed by cell proliferation. We found through analyzing the mitochondrial proteome that GLS was increased dramatically in response to c-Myc induction. siRNA targeting GLS1 diminishes cell proliferation and increased apoptosis, indicating that GLS1 is necessary for Myc induced cell proliferation. GLS converts glutamine to glutamate that is further catabolized through the TCA cycle for the production of ATP or serves as substrate for glutathione synthesis. In this regard, depletion of glutamine significantly diminished proliferation of P-493 cell and the human prostate PC3 cancer cell line. Although GLS protein levels are induced >10-fold by c-Myc in P-493 cells, GLS1 mRNA did not vary significantly, suggesting that regulation of GLS protein levels by c-Myc is post-transcriptional. We document that c-Myc transcriptionally represses miR-23, which can inhibit the expression of GLS protein through targeting the 3\#8217;UTR. In addition to the responses of wild-type and miR-23 seed sequence mutant luciferase-GLS1-3\#8217;UTR reporter constructs, antisense miR-23 LNA oligonucleotides were able to elevate GLS protein levels in low c-Myc expressing P493 and PC3 cells, indicating that GLS1 mRNA is a target of miR-23 that inhibits glutaminase translation. Since miR-23 expression is decreased in human prostate cancer, we immunoblotted and found a correlation between c-Myc and GLS protein levels in human prostate cancer samples as compared with lowered expression in the corresponding normal prostate tissues. The unique means by which Myc regulates GLS uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species (ROS) homeostasis and provides a regulatory mechanism involving c-Myc and miRNAs for elevated expression of glutaminase and glutamine metabolism in human cancers. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-186.
TL;DR: The role of AR in androgen-independent cancer cells is not to direct the androgen -dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgens-independent growth.
TL;DR: Hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming, and mediates maladaptive responses to chronic continuous and intermittent hypoxIA, which underlie the development of pulmonary and systemic hypertension.
Abstract: Metazoan organisms are dependent on a continuous supply of O2 for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in dev...
TL;DR: High-content chemical screening is used to identify small molecules that can replace Sox2 in reprogramming and it is found that one of these molecules functions inReprogramming by inhibiting Tgf-beta signaling in a stable and trapped intermediate cell type that forms during the process.
TL;DR: Ectopic MYC expression in cancers could concurrently drive aerobic glycolysis and/or oxidative phosphorylation to provide sufficient energy and anabolic substrates for cell growth and proliferation in the context of the tumor microenvironment.
Abstract: Although cancers have altered glucose metabolism, termed the Warburg effect, which describes the increased uptake and conversion of glucose to lactate by cancer cells under adequate oxygen tension, changes in the metabolism of glutamine and fatty acid have also been documented. The MYC oncogene, which contributes to the genesis of many human cancers, encodes a transcription factor c-Myc, which links altered cellular metabolism to tumorigenesis. c-Myc regulates genes involved in the biogenesis of ribosomes and mitochondria, and regulation of glucose and glutamine metabolism. With E2F1, c-Myc induces genes involved in nucleotide metabolism and DNA replication, and microRNAs that homeostatically attenuate E2F1 expression. With the hypoxia inducible transcription factor HIF-1, ectopic c-Myc cooperatively induces a transcriptional program for hypoxic adaptation. Myc regulates gene expression either directly, such as glycolytic genes including lactate dehydrogenase A (LDHA), or indirectly, such as repression of microRNAs miR-23a/b to increase glutaminase (GLS) protein expression and glutamine metabolism. Ectopic MYC expression in cancers, therefore, could concurrently drive aerobic glycolysis and/or oxidative phosphorylation to provide sufficient energy and anabolic substrates for cell growth and proliferation in the context of the tumor microenvironment. Collectively, these studies indicate that Myc-mediated altered cancer cell energy metabolism could be translated for the development of new anticancer therapies.
TL;DR: Understanding of how the transcription factor is regulated indicates ways in which drug resistance in tumours could be overcome and Somatic mutations in KEAP1 and NRF2 provide an insight into the molecular mechanisms by whichNRF2 is regulated.
TL;DR: It is found that Foxp3 controlled the elevated miR155 expression required for maintaining Treg cell proliferative activity and numbers under nonlymphopenic conditions and provides experimental support for a proposed role for miRNAs in ensuring the robustness of cellular phenotypes.
TL;DR: It is shown that addition of the FLC antisense promoter sequences to a reporter gene is sufficient to confer cold-induced silencing of the reporter, and upregulation of long non-coding antisense transcripts covering the entire FLC locus may be part of the cold-sensing mechanism.
Abstract: Transcription in eukaryotic genomes generates an extensive array of non-protein-coding RNA, the functional significance of which is mostly unknown. We are investigating the link between non-coding RNA and chromatin regulation through analysis of FLC - a regulator of flowering time in Arabidopsis and a target of several chromatin pathways. Here we use an unbiased strategy to characterize non-coding transcripts of FLC and show that sense/antisense transcript levels correlate in a range of mutants and treatments, but change independently in cold-treated plants. Prolonged cold epigenetically silences FLC in a Polycomb-mediated process called vernalization. Our data indicate that upregulation of long non-coding antisense transcripts covering the entire FLC locus may be part of the cold-sensing mechanism. Induction of these antisense transcripts occurs earlier than, and is independent of, other vernalization markers and coincides with a reduction in sense transcription. We show that addition of the FLC antisense promoter sequences to a reporter gene is sufficient to confer cold-induced silencing of the reporter. Our data indicate that cold-induced FLC antisense transcripts have an early role in the epigenetic silencing of FLC, acting to silence FLC transcription transiently. Recruitment of the Polycomb machinery then confers the epigenetic memory. Antisense transcription events originating from 3' ends of genes might be a general mechanism to regulate the corresponding sense transcription in a condition/stage-dependent manner.
TL;DR: Relevant studies in lower vertebrates indicate the conservation and divergence of regulatory mechanisms for cell lineage allocation and axis patterning in the early mammalian embryo.
Abstract: Genetic studies have identified the key signalling pathways and developmentally regulated transcription factors that govern cell lineage allocation and axis patterning in the early mammalian embryo. Recent advances have uncovered details of the molecular circuits that tightly control cell growth and differentiation in the mammalian embryo from the blastocyst stage, through the establishment of initial anterior-posterior polarity, to gastrulation, when the germ cells are set aside and the three primary germ layers are specified. Relevant studies in lower vertebrates indicate the conservation and divergence of regulatory mechanisms for cell lineage allocation and axis patterning.
TL;DR: Insights are revealed about how IFN-gamma regulates macrophage activation, inflammation, tissue remodeling, and helper and regulatory T cell differentiation and how Th1 and Th17 cell responses are integrated in autoimmune diseases.
TL;DR: It is demonstrated that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex at a critical protein–protein interface in the NOTCH transactivation complex.
Abstract: Direct inhibition of transcription factor complexes remains a central challenge in the discipline of ligand discovery. In general, these proteins lack surface involutions suitable for high-affinity binding by small molecules. Here we report the design of synthetic, cell-permeable, stabilized α-helical peptides that target a critical protein–protein interface in the NOTCH transactivation complex. We demonstrate that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL). The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL. The NOTCH complex is of tremendous interest because of its role as a master developmental regulator of gene transcription, a substrate for γ-secretase and an oncogene inappropriately activated in many cancers including T-cell leukaemias. Like the majority of transcription factors, NOTCH was thought to be untargetable by synthetic cell-permeable molecules. But now a promising NOTCH antagonist has been designed, and found to be effective in reducing leukaemia growth in a mouse model. The hydrocarbon-stapled peptide SAHM1 acts by preventing assembly of the active transcriptional complex, providing a potentially valuable tool for studies of the role of NOTCH and a starting point for therapeutic agents. In addition, the direct targeting of transactivation complexes may be applicable to several other transcription factor complexes previously considered untargetable. It is notoriously difficult to target transcription factors with aberrant activity in cancer. Inappropriate activation of the NOTCH complex of transcription factors is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia. The design of synthetic, cell-permeable, stabilized α-helical peptides that disrupt protein–protein interactions in NOTCH is now described.
TL;DR: It is shown that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity and establishes a role for SIRT1 in protein homeostasis and the HSR.
Abstract: Heat shock factor 1 (HSF1) is essential for protecting cells from protein-damaging stress associated with misfolded proteins and regulates the insulin-signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA–binding competent state. Conversely, down-regulation of SIRT1 accelerated the attenuation of the heat shock response (HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.
TL;DR: The results indicate that MYB58 and MYB63 are specific transcriptional activators of lignin biosynthesis in the SND1-mediated transcriptional network regulating secondary wall formation.
Abstract: It has previously been shown that SECONDARY WALL–ASSOCIATED NAC DOMAIN PROTEIN1 (SND1) is a key transcription factor regulating secondary cell wall formation, including the biosynthesis of cellulose, xylan, and lignin. In this study, we show that two closely related SND1-regulated MYB transcription factors, MYB58 and MYB63, are transcriptional regulators specifically activating lignin biosynthetic genes during secondary wall formation in Arabidopsis thaliana. MYB58 and MYB63 are phylogenetically distinct from previously characterized MYBs shown to be associated with secondary wall formation or phenylpropanoid metabolism. Expression studies showed that MYB58 and MYB63 are specifically expressed in fibers and vessels undergoing secondary wall thickening. Dominant repression of their functions led to a reduction in secondary wall thickening and lignin content. Overexpression of MYB58 and MYB63 resulted in specific activation of lignin biosynthetic genes and concomitant ectopic deposition of lignin in cells that are normally unlignified. MYB58 was able to activate directly the expression of lignin biosynthetic genes and a secondary wall–associated laccase (LAC4) gene. Furthermore, the expression of MYB58 and MYB63 was shown to be regulated by the SND1 close homologs NST1, NST2, VND6, and VND7 and their downstream target MYB46. Together, our results indicate that MYB58 and MYB63 are specific transcriptional activators of lignin biosynthesis in the SND1-mediated transcriptional network regulating secondary wall formation.