scholarly journals Corepressors: Custom Tailoring and Alterations While you Wait

2005 ◽  
Vol 3 (1) ◽  
pp. nrs.03003 ◽  
Author(s):  
Michael Goodson ◽  
Brian A. Jonas ◽  
Martin A. Privalsky
Keyword(s):  
Transcription Factor ◽  
Transcriptional Repression ◽  
Developmental Stages ◽  
Thyroid Hormone Receptor ◽  
Protein Complexes ◽  
Biological Properties ◽  
Mrna Splicing ◽  
Alternative Mrna Splicing ◽  
Splicing Variants ◽  
Protein Variants

A diverse cadre of metazoan transcription factors mediate repression by recruiting protein complexes containing the SMRT (silencing mediator of retinoid and thyroid hormone receptor) or N-CoR (nuclear receptor corepressor) corepressors. SMRT and N-CoR nucleate the assembly of still larger corepressor complexes that perform the specific molecular incantations necessary to confer transcriptional repression. Although SMRT and N-CoR are paralogs and possess similar molecular architectures and mechanistic strategies, they nonetheless exhibit distinct molecular and biological properties. It is now clear that the functions of both SMRT and N-CoR are further diversified through alternative mRNA splicing, yielding a series of corepressor protein variants that participate in distinctive transcription factor partnerships and display distinguishable repression properties. This review will discuss what is known about the structure and actions of SMRT, N-CoR, and their splicing variants, and how alternative splicing may allow the functions of these corepressors to be adapted and tailored to different cells and to different developmental stages.

scholarly journals Alternative mRNA splicing of SAP30L regulates its transcriptional repression activity

FEBS Letters ◽  
2007 ◽  
Vol 582 (2) ◽  
pp. 379-384 ◽  
Author(s):  
Hanna Korkeamäki ◽  
Keijo Viiri ◽  
Mari K. Kukkonen ◽  
Markku Mäki ◽  
Olli Lohi
Keyword(s):  
Transcriptional Repression ◽  
Mrna Splicing ◽  
Alternative Mrna Splicing

scholarly journals Response of SMRT (Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor) and N-CoR (Nuclear Receptor Corepressor) Corepressors to Mitogen-Activated Protein Kinase Kinase Kinase Cascades Is Determined by Alternative mRNA Splicing

2007 ◽  
Vol 21 (8) ◽  
pp. 1924-1939 ◽  
Author(s):  
Brian A. Jonas ◽  
Natalia Varlakhanova ◽  
Fumihiko Hayakawa ◽  
Michael Goodson ◽  
Martin L. Privalsky
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Nuclear Receptor ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Splice Variants ◽  
Mrna Splicing ◽  
Alternative Mrna Splicing ◽  
Nuclear Receptor Corepressor ◽  
Erk Kinase

Abstract The SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) corepressors are important mediators of transcriptional repression by nuclear hormone receptors. SMRT is regulated by MAPK kinase kinase (MAPKKK) cascades that induce its release from its receptor partners, its export from nucleus to cytoplasm, and derepression of target gene expression. Intriguingly, the otherwise closely related N-CoR is refractory to MAPKKK signaling under the same conditions. However, both SMRT and N-CoR are expressed as a series of alternatively spliced protein variants differing in structure and function. We have now characterized the impact of this alternative mRNA splicing on the corepressor response to MAPKKK signaling. Whereas the SMRTα, SMRTτ, and SMRTsp2 splice variants are released from their nuclear receptor partners in response to MAPKKK activation, the SMRTsp18 variant, which resembles N-CoR in its overall molecular architecture, is relatively refractory to this kinase-induced release. Alternative splicing of N-CoR, in contrast, had only minimal effects on the resistance of this corepressor to MAPKKK inhibition. Notably, all of the SMRT splice variants examined redistributed from nucleus to cytoplasm in response to MAPKKK cascade signaling, but none of the N-CoR splice variants did so. Different tiers of the MAPKKK cascade hierarchy contributed to these different aspects of corepressor regulation, with MAP/ERK kinase kinase 1 and MAP/ERK kinase 1 regulating subcellular redistribution and ERK2 regulating nuclear receptor-corepressor interaction. We conclude that cells can customize their transcriptional response to MAPKKK cascade signaling by selective expression of the SMRT or N-CoR locus, by selective utilization of a specific corepressor splice variant, and by selective exploitation of specific tiers of the MAPK cascade.

scholarly journals Orchestration of Primary Hemostasis by Platelet and Endothelial Lysosome-Related Organelles

2020 ◽  
Vol 40 (6) ◽  
pp. 1441-1453 ◽  
Author(s):  
Ellie Karampini ◽  
Ruben Bierings ◽  
Jan Voorberg
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Protein Complexes ◽  
Biological Properties ◽  
Bleeding Disorders ◽  
Granule Formation ◽  
Primary Hemostasis ◽  
Granule Maturation ◽  
Lysosome Related Organelles ◽  
Von Willebrand

Megakaryocyte-derived platelets and endothelial cells store their hemostatic cargo in α- and δ-granules and Weibel-Palade bodies, respectively. These storage granules belong to the lysosome-related organelles (LROs), a heterogeneous group of organelles that are rapidly released following agonist-induced triggering of intracellular signaling pathways. Following vascular injury, endothelial Weibel-Palade bodies release their content into the vascular lumen and promote the formation of long VWF (von Willebrand factor) strings that form an adhesive platform for platelets. Binding to VWF strings as well as exposed subendothelial collagen activates platelets resulting in the release of α- and δ-granules, which are crucial events in formation of a primary hemostatic plug. Biogenesis and secretion of these LROs are pivotal for the maintenance of proper hemostasis. Several bleeding disorders have been linked to abnormal generation of LROs in megakaryocytes and endothelial cells. Recent reviews have emphasized common pathways in the biogenesis and biological properties of LROs, focusing mainly on melanosomes. Despite many similarities, LROs in platelet and endothelial cells clearly possess distinct properties that allow them to provide a highly coordinated and synergistic contribution to primary hemostasis by sequentially releasing hemostatic cargo. In this brief review, we discuss in depth the known regulators of α- and δ-granules in megakaryocytes/platelets and Weibel-Palade bodies in endothelial cells, starting from transcription factors that have been associated with granule formation to protein complexes that promote granule maturation. In addition, we provide a detailed view on the interplay between platelet and endothelial LROs in controlling hemostasis as well as their dysfunction in LRO related bleeding disorders.

Novel aspects of endometrial function: a biological sensor of embryo quality and driver of pregnancy success

2012 ◽  
Vol 24 (1) ◽  
pp. 68 ◽  
Author(s):  
Olivier Sandra ◽  
Nadéra Mansouri-Attia ◽  
Richard G. Lea
Keyword(s):  
Developmental Stages ◽  
Assisted Reproductive Technologies ◽  
Uterine Cavity ◽  
Reproductive Technologies ◽  
Biological Properties ◽  
Reproductive Capacity ◽  
Epigenetic Alterations ◽  
Uterine Receptivity ◽  
Blastocyst Development ◽  
Developmental Potential

Successful pregnancy depends on complex biological processes that are regulated temporally and spatially throughout gestation. The molecular basis of these processes have been examined in relation to gamete quality, early blastocyst development and placental function, and data have been generated showing perturbations of these developmental stages by environmental insults or embryo biotechnologies. The developmental period falling between the entry of the blastocyst into the uterine cavity to implantation has also been examined in terms of the biological function of the endometrium. Indeed several mechanisms underlying uterine receptivity, controlled by maternal factors, and the maternal recognition of pregnancy, requiring conceptus-produced signals, have been clarified. Nevertheless, recent data based on experimental perturbations have unveiled unexpected biological properties of the endometrium (sensor/driver) that make this tissue a dynamic and reactive entity. Persistent or transient modifications in organisation and functionality of the endometrium can dramatically affect pre-implantation embryo trajectory through epigenetic alterations with lasting consequences on later stages of pregnancy, including placentation, fetal development, pregnancy outcome and post-natal health. Developing diagnostic and prognostic tools based on endometrial factors may enable the assessment of maternal reproductive capacity and/or the developmental potential of the embryo, particularly when assisted reproductive technologies are applied.

scholarly journals Characterization of Receptor Interaction and Transcriptional Repression by the Corepressor SMRT

1997 ◽  
Vol 11 (13) ◽  
pp. 2025-2037 ◽  
Author(s):  
Hui Li ◽  
Christopher Leo ◽  
Daniel J. Schroen ◽  
J. Don Chen
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Transcriptional Repression ◽  
Thyroid Hormone Receptor ◽  
Receptor Interaction ◽  
Basal Transcription ◽  
Protein Protein Interaction ◽  
Stable Association ◽  
Interacting Surfaces ◽  
Transcriptional Corepressors

Abstract SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) are two related transcriptional corepressors that contain separable domains capable of interacting with unliganded nuclear receptors and repressing basal transcription. To decipher the mechanisms of receptor interaction and transcriptional repression by SMRT/N-CoR, we have characterized protein-protein interacting surfaces between SMRT and nuclear receptors and defined transcriptional repression domains of both SMRT and N-CoR. Deletional analysis reveals two individual nuclear receptor domains necessary for stable association with SMRT and a C-terminal helix essential for corepressor dissociation. Coordinately, two SMRT domains are found to interact independently with the receptors. Functional analysis reveals that SMRT contains two distinct repression domains, and the corresponding regions in N-CoR also repress basal transcription. Both repression domains in SMRT and N-CoR interact weakly with mSin3A, which in turn associates with a histone deacetylase HDAC1 in a mammalian two-hybrid assay. Far-Western analysis demonstrates a direct protein-protein interaction between two N-CoR repression domains with mSin3A. Finally we demonstrate that overexpression of full-length SMRT further represses basal transcription from natural promoters. Together, these results support a role of SMRT/N-CoR in corepression through the utilization of multiple mechanisms for receptor interactions and transcriptional repression.

The functional relationship between co-repressor N-CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor α

2008 ◽  
Vol 411 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Kyung-Chul Choi ◽  
So-Young Oh ◽  
Hee-Bum Kang ◽  
Yoo-Hyun Lee ◽  
Seungjoo Haam ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Transcriptional Repression ◽  
Fatty Acid Synthase ◽  
Hormone Receptors ◽  
Target Genes ◽  
Functional Relationship ◽  
Thyroid Hormone Receptor ◽  
B Cell Lymphoma ◽  
Hormone Response Elements

A central issue in mediating repression by nuclear hormone receptors is the distinct or redundant function between co-repressors N-CoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor). To address the functional relationship between SMRT and N-CoR in TR (thyroid hormone receptor)-mediated repression, we have identified multiple TR target genes, including BCL3 (B-cell lymphoma 3-encoded protein), Spot14 (thyroid hormone-inducible hepatic protein), FAS (fatty acid synthase), and ADRB2 (β-adrenergic receptor 2). We demonstrated that siRNA (small interfering RNA) treatment against either N-CoR or SMRT is sufficient for the de-repression of multiple TR target genes. By the combination of sequence mining and physical association as determined by ChIP (chromatin immunoprecipitation) assays, we mapped the putative TREs (thyroid hormone response elements) in BCL3, Spot14, FAS and ADRB2 genes. Our data clearly show that SMRT and N-CoR are independently recruited to various TR target genes. We also present evidence that overexpression of N-CoR can restore repression of endogenous genes after knocking down SMRT. Finally, unliganded, co-repressor-free TR is defective in repression and interacts with a co-activator, p300. Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes.

scholarly journals Repression of ESR1 through Actions of Estrogen Receptor Alpha and Sin3A at the Proximal Promoter

2009 ◽  
Vol 29 (18) ◽  
pp. 4949-4958 ◽  
Author(s):  
Stephanie J. Ellison-Zelski ◽  
Natalia M. Solodin ◽  
Elaine T. Alarid
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Rna Polymerase Ii ◽  
Transcriptional Repression ◽  
Estrogen Receptor Alpha ◽  
Proximal Promoter ◽  
Receptor Alpha ◽  
Expression Of Genes ◽  
Activation Of Transcription

ABSTRACT Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor alpha (ERα) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation of transcription by estrogen-bound ERα has been studied in detail, as has antagonist-induced repression, such as that which occurs by tamoxifen. How estrogen-bound ERα represses gene transcription remains unclear. In this report, we identify a new mechanism of estrogen-induced transcriptional repression by using the ERα gene, ESR1. Upon estrogen treatment, ERα is recruited to two sites on ESR1, one distal (ENH1) and the other at the proximal (A) promoter. Coactivator proteins, namely, p300 and AIB1, are found at both ERα-binding sites. However, recruitment of the Sin3A repressor, loss of RNA polymerase II, and changes in histone modifications occur only at the A promoter. Reduction of Sin3A expression by RNA interference specifically inhibits estrogen-induced repression of ESR1. Furthermore, an estrogen-responsive interaction between Sin3A and ERα is identified. These data support a model of repression wherein actions of ERα and Sin3A at the proximal promoter can overcome activating signals at distal or proximal sites and ultimately decrease gene expression.

Regulation of yeast COX6 by the general transcription factor ABF1 and separate HAP2- and heme-responsive elements

1992 ◽  
Vol 12 (5) ◽  
pp. 2302-2314
Author(s):  
J D Trawick ◽  
N Kraut ◽  
F R Simon ◽  
R O Poyton
Keyword(s):  
Transcription Factor ◽  
Carbon Source ◽  
Protein Binding ◽  
Glucose Repression ◽  
Protein Complexes ◽  
Carbon Sources ◽  
Major Protein ◽  
Mobility Shift ◽  
Gel Mobility Shift ◽  
In Cells

Transcription of the Saccharomyces cerevisiae COX6 gene is regulated by heme and carbon source. It is also affected by the HAP2/3/4 transcription factor complex and by SNF1 and SSN6. Previously, we have shown that most of this regulation is mediated through UAS6, an 84-bp upstream activation segment of the COX6 promoter. In this study, by using linker scanning mutagenesis and protein binding assays, we have identified three elements within UAS6 and one element downstream of it that are important. Two of these, HDS1 (heme-dependent site 1; between -269 and -251 bp) and HDS2 (between -228 and -220 bp), mediate regulation of COX6 by heme. Both act negatively. The other two elements, domain 2 (between -279 and -269 bp) and domain 1 (between -302 and -281 bp), act positively. Domain 2 is required for optimal transcription in cells grown in repressing but not derepressing carbon sources. Domain 1 is essential for transcription per se in cells grown on repressing carbon sources, is required for optimal transcription in cells grown on a derepressing carbon source, is sufficient for glucose repression-derepression, and is the element of UAS6 at which HAP2 affects COX6 transcription. This element contains the major protein binding sites within UAS6. It has consensus binding sequences for ABF1 and HAP2. Gel mobility shift experiments show that domain 1 binds ABF1 and forms different numbers of DNA-protein complexes in extracts from cells grown in repressing or derepressing carbon sources. In contrast, gel mobility shift experiments have failed to reveal that HAP2 or HAP3 binds to domain 1 or that hap3 mutations affect the complexes bound to it. Together, these findings permit the following conclusions: COX6 transcription is regulated both positively and negatively; heme and carbon source exert their effects through different sites; domain 1 is absolutely essential for transcription on repressing carbon sources; ABF1 is a major component in the regulation of COX6 transcription; and the HAP2/3/4 complex most likely affects COX6 transcription indirectly.

scholarly journals Corepressor diversification by alternative mRNA splicing is species specific

2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Martin L. Privalsky ◽  
Chelsea A. Snyder ◽  
Michael L. Goodson
Keyword(s):  
Mrna Splicing ◽  
Alternative Mrna Splicing ◽  
Species Specific

scholarly journals YY1 plays an essential role at all stages of B-cell differentiation

2016 ◽  
Vol 113 (27) ◽  
pp. E3911-E3920 ◽  
Author(s):  
Eden Kleiman ◽  
Haiqun Jia ◽  
Salvatore Loguercio ◽  
Andrew I. Su ◽  
Ann J. Feeney
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Signaling Pathways ◽  
Mrna Splicing ◽  
Cell Populations ◽  
Sequencing Analysis ◽  
B Cell Differentiation ◽  
Chip Sequencing

Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor shown to be essential for pro–B-cell development. However, the role of YY1 in other B-cell populations has never been investigated. Recent bioinformatics analysis data have implicated YY1 in the germinal center (GC) B-cell transcriptional program. In accord with this prediction, we demonstrated that deletion of YY1 by Cγ1-Cre completely prevented differentiation of GC B cells and plasma cells. To determine if YY1 was also required for the differentiation of other B-cell populations, we deleted YY1 with CD19-Cre and found that all peripheral B-cell subsets, including B1 B cells, require YY1 for their differentiation. Transitional 1 (T1) B cells were the most dependent upon YY1, being sensitive to even a half-dosage of YY1 and also to short-term YY1 deletion by tamoxifen-induced Cre. We show that YY1 exerts its effects, in part, by promoting B-cell survival and proliferation. ChIP-sequencing shows that YY1 predominantly binds to promoters, and pathway analysis of the genes that bind YY1 show enrichment in ribosomal functions, mitochondrial functions such as bioenergetics, and functions related to transcription such as mRNA splicing. By RNA-sequencing analysis of differentially expressed genes, we demonstrated that YY1 normally activates genes involved in mitochondrial bioenergetics, whereas it normally down-regulates genes involved in transcription, mRNA splicing, NF-κB signaling pathways, the AP-1 transcription factor network, chromatin remodeling, cytokine signaling pathways, cell adhesion, and cell proliferation. Our results show the crucial role that YY1 plays in regulating broad general processes throughout all stages of B-cell differentiation.

Sign in / Sign up

Export Citation Format

Share Document