scholarly journals Activator-to-Repressor Conversion of T-Box Transcription Factors by the Ripply Family of Groucho/TLE-Associated Mediators

2008 ◽  
Vol 28 (10) ◽  
pp. 3236-3244 ◽  
Author(s):  
Akinori Kawamura ◽  
Sumito Koshida ◽  
Shinji Takada
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Cultured Cells ◽  
Biological Significance ◽  
Zebrafish Embryos ◽  
Mutant Form ◽  
Dna Binding Domain ◽  
T Box ◽  
No Tail ◽  
Posterior Trunk

ABSTRACT The T-box family of transcription factors, defined by a conserved DNA binding domain called the T-box, regulate various aspects of embryogenesis by activating and/or repressing downstream genes. In spite of the biological significance of the T-box proteins, how they regulate transcription remains to be elucidated. Here we show that the Groucho/TLE-associated protein Ripply converts T-box proteins from activators to repressors. In cultured cells, zebrafish Ripply1, an essential component in somite segmentation, and its structural relatives, Ripply2 and -3, suppress the transcriptional activation mediated by the T-box protein Tbx24, which is coexpressed with ripply1 during segmentation. Ripply1 associates with Tbx24 and converts it to a repressor. Ripply1 also antagonizes the transcriptional activation of another T-box protein, No tail (Ntl), the zebrafish ortholog of Brachyury. Furthermore, injection of a high dosage of ripply1 mRNA into zebrafish eggs causes defective development of the posterior trunk, similar to the phenotype observed in homozygous mutants of ntl. A mutant form of Ripply1 defective in association with Tbx24 also lacks activity in zebrafish embryos. These results indicate that the intrinsic transcriptional property of T-box proteins is controlled by Ripply family proteins, which act as specific adaptors that recruit the global corepressor Groucho/TLE to T-box proteins.

scholarly journals Single-molecule dynamics and genome-wide transcriptomics reveal that NF-κB (p65)-DNA binding times can be decoupled from transcriptional activation

2018 ◽  
Author(s):  
Andrea Callegari ◽  
Christian Sieben ◽  
Alexander Benke ◽  
David M. Suter ◽  
Beat Fierz ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Single Molecule ◽  
Protein Interaction ◽  
Transcriptional Activation ◽  
Dna Binding Domain ◽  
Protein Protein Interaction ◽  
Genome Wide ◽  
Binding Time ◽  
Transcriptional Output

AbstractTranscription factors (TFs) regulate gene expression in both prokaryotes and eukaryotes by recognizing and binding to specific DNA promoter sequences. In higher eukaryotes, it remains unclear how the duration of TF binding to DNA relates to downstream transcriptional output. Here, we address this question for the transcriptional activator NF-κB (p65), by live-cell single molecule imaging of TF-DNA binding kinetics and genome-wide quantification of p65-mediated transcription. We used mutants of p65, perturbing either the DNA binding domain (DBD) or the protein-protein transactivation domain (TAD). We found that p65-DNA binding time was predominantly determined by its DBD and directly correlated with its transcriptional output as long as the TAD is intact. Surprisingly, mutation or deletion of the TAD did not modify p65-DNA binding stability, suggesting that the p65 TAD generally contributes neither to the assembly of an “enhanceosome,” nor to the active removal of p65 from putative specific binding sites. However, TAD removal did reduce p65-mediated transcriptional activation, indicating that protein-protein interactions act to translate the long-lived p65-DNA binding into productive transcription.Author SummaryTo control transcription of a certain gene or a group of genes, both eukaryotes and prokaryotes express specialized proteins, transcription factors (TFs). During gene activation, TFs bind gene promotor sequences to recruit the transcriptional machinery including DNA polymerase II. TFs are often multi-subunit proteins containing a DNA-binding domain (DBD) as well as a protein-protein interaction interface. It was suggested that the duration of a TF-DNA binding event 1) depends on these two subunits and 2) dictates the outcome, i.e. the amount of mRNA produced from an activated gene. We set out to address these hypotheses using the transcriptional activator NF-κB (p65) as well as a number of mutants affecting different functional subunits. Using a combination of live-cell microscopy and RNA sequencing, we show that p65 DNA-binding time indeed correlates with the transcriptional output, but that this relationship depends on, and hence can be uncoupled by altering, the protein-protein interaction capacity. Our results suggest that, while p65 DNA binding times are dominated by the DBD, a transcriptional output can only be achieved with a functional protein-protein interaction subunit.

Molecular identification of spadetail: regulation of zebrafish trunk and tail mesoderm formation by T-box genes

Development ◽  
1998 ◽  
Vol 125 (17) ◽  
pp. 3379-3388 ◽  
Author(s):  
K.J. Griffin ◽  
S.L. Amacher ◽  
C.B. Kimmel ◽  
D. Kimelman
Keyword(s):  
Transcription Factor ◽  
Genetic Model ◽  
Zebrafish Embryos ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
T Box ◽  
Tail Development ◽  
No Tail ◽  
Mesoderm Formation ◽  
Complementary Actions

Inhibition of fibroblast growth factor (FGF) signaling prevents trunk and tail formation in Xenopus and zebrafish embryos. While the T-box transcription factor Brachyury (called No Tail in zebrafish) is a key mediator of FGF signaling in the notochord and tail, the pathways activated by FGF in non-notochordal trunk mesoderm have been uncertain. Previous studies have shown that the spadetail gene is required for non-notochordal trunk mesoderm formation; spadetail mutant embryos have major trunk mesoderm deficiencies, but relatively normal tail and notochord development. We demonstrate here that spadetail encodes a T-box transcription factor with homologues in Xenopus and chick. Spadetail is likely to be a key mediator of FGF signaling in trunk non-notochordal mesoderm, since spadetail expression is regulated by FGF signaling. Trunk and tail development are therefore dependent upon the complementary actions of two T-box genes, spadetail and no tail. We show that the regulatory hierarchy among spadetail, no tail and a third T-box gene, tbx6, are substantially different during trunk and tail mesoderm formation, and propose a genetic model that accounts for the regional phenotypes of spadetail and no tail mutants.

Determinants of T box protein specificity

Development ◽  
2001 ◽  
Vol 128 (19) ◽  
pp. 3749-3758 ◽  
Author(s):  
Frank L. Conlon ◽  
Lynne Fairclough ◽  
Brenda M. J. Price ◽  
Elena S. Casey ◽  
J. C. Smith
Keyword(s):  
Transcription Factors ◽  
Amino Acid ◽  
Dna Binding ◽  
Binding Site ◽  
Early Development ◽  
Site Selection ◽  
Dna Binding Domain ◽  
T Box ◽  
The Family ◽  
Selection Experiments

Members of the T box family of transcription factors play important roles in early development. Different members of the family exert different effects and here we show that much of the specificity of the Xenopus T box proteins Xbra, VegT and Eomesodermin resides in the DNA-binding domain, or T box. Binding site selection experiments show that the three proteins bind the same core sequence, but they select paired sites that differ in their orientation and spacing. Lysine 149 of Xbra is conserved in all Brachyury homologues, while the corresponding amino acid in VegT and Eomesodermin is asparagine. Mutation of this amino acid to lysine changes the inductive abilities of VegT and Eomesodermin to resemble that of Xbra.

Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression

2005 ◽  
Vol 83 (4) ◽  
pp. 535-547 ◽  
Author(s):  
Gareth N Corry ◽  
D Alan Underhill
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Current Knowledge ◽  
Nuclear Architecture ◽  
Subnuclear Localization ◽  
Modular Structures

To date, the majority of the research regarding eukaryotic transcription factors has focused on characterizing their function primarily through in vitro methods. These studies have revealed that transcription factors are essentially modular structures, containing separate regions that participate in such activities as DNA binding, protein–protein interaction, and transcriptional activation or repression. To fully comprehend the behavior of a given transcription factor, however, these domains must be analyzed in the context of the entire protein, and in certain cases the context of a multiprotein complex. Furthermore, it must be appreciated that transcription factors function in the nucleus, where they must contend with a variety of factors, including the nuclear architecture, chromatin domains, chromosome territories, and cell-cycle-associated processes. Recent examinations of transcription factors in the nucleus have clarified the behavior of these proteins in vivo and have increased our understanding of how gene expression is regulated in eukaryotes. Here, we review the current knowledge regarding sequence-specific transcription factor compartmentalization within the nucleus and discuss its impact on the regulation of such processes as activation or repression of gene expression and interaction with coregulatory factors.Key words: transcription, subnuclear localization, chromatin, gene expression, nuclear architecture.

scholarly journals Evolution of Mouse T-box Genes by Tandem Duplication and Cluster Dispersion

Genetics ◽  
1996 ◽  
Vol 144 (1) ◽  
pp. 249-254 ◽  
Author(s):  
Sergei I Agulnik ◽  
Nancy Garvey ◽  
Sarah Hancock ◽  
Ilya Ruvinsky ◽  
Deborah L Chapman ◽  
...  
Keyword(s):  
Tandem Duplication ◽  
Crossing Over ◽  
Dna Binding Domain ◽  
Gene Products ◽  
New Members ◽  
Ancestral Gene ◽  
T Box ◽  
Temporal And Spatial Patterns ◽  
Temporal And Spatial ◽  
T Locus

Abstract The T-box genes comprise an ancient family of putative transcription factors conserved across species as divergent as Mus musculus and Caenorhabditis elegans. All T-box gene products are characterized by a novel 174-186amino acid DNA binding domain called the T-box that was first discovered in the polypeptide products of the mouse T locus and the Drosophila melanogaster optomotor-blind gene. Earlier studies allowed the identification of five mouse T-box genes, T, Tbx1-3, and Tbr1, that all map to different chromosomal locations and are expressed in unique temporal and spatial patterns during embryogenesis. Here, we report the discovery of three new members of the mouse T-box gene family, named Tbx4, Tbx5, and Tbx6. Two of these newly discovered genes, Tbx4 and Tbx5, were found to be tightly linked to previously identified T-box genes. Combined results from phylogenetic, linkage, and physical mapping studies provide a picture for the evolution of a T-box subfamily by unequal crossing over to form a two-gene cluster that was duplicated and dispersed to two chromosomal locations. This analysis suggests that Tbx4 and Tbx5 are cognate genes that diverged apart from a common ancestral gene during early vertebrate evolution.

scholarly journals RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry

2012 ◽  
Vol 209 (13) ◽  
pp. 2409-2422 ◽  
Author(s):  
Heiyoun Jung ◽  
Benjamin Hsiung ◽  
Kathleen Pestal ◽  
Emily Procyk ◽  
David H. Raulet
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Stress Responses ◽  
Transcriptional Activation ◽  
Posttranscriptional Regulation ◽  
Cellular Proliferation ◽  
Control Cell ◽  
T Cell Subsets ◽  
Cell Cycle Entry

The NKG2D stimulatory receptor expressed by natural killer cells and T cell subsets recognizes cell surface ligands that are induced on transformed and infected cells and facilitate immune rejection of tumor cells. We demonstrate that expression of retinoic acid early inducible gene 1 (RAE-1) family NKG2D ligands in cancer cell lines and proliferating normal cells is coupled directly to cell cycle regulation. Raet1 genes are directly transcriptionally activated by E2F family transcription factors, which play a central role in regulating cell cycle entry. Induction of RAE-1 occurred in primary cell cultures, embryonic brain cells in vivo, and cells in healing skin wounds and, accordingly, wound healing was delayed in mice lacking NKG2D. Transcriptional activation by E2Fs is likely coordinated with posttranscriptional regulation by other stress responses. These findings suggest that cellular proliferation, as occurs in cancer cells but also other pathological conditions, is a key signal tied to immune reactions mediated by NKG2D-bearing lymphocytes.

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