Activation Functions 1 and 2 of Nuclear Receptors: Molecular Strategies for Transcriptional Activation

2003 ◽  
Vol 17 (10) ◽  
pp. 1901-1909 ◽  
Author(s):  
Anette Wärnmark ◽  
Eckardt Treuter ◽  
Anthony P. H. Wright ◽  
Jan-Åke Gustafsson
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Preinitiation Complex ◽  
Activation Domains ◽  
Terminal Domain

Abstract Nuclear receptors (NRs) comprise a family of ligand inducible transcription factors. To achieve transcriptional activation of target genes, DNA-bound NRs directly recruit general transcription factors (GTFs) to the preinitiation complex or bind intermediary factors, so-called coactivators. These coactivators often constitute subunits of larger multiprotein complexes that act at several functional levels, such as chromatin remodeling, enzymatic modification of histone tails, or modulation of the preinitiation complex via interactions with RNA polymerase II and GTFs. The binding of NR to coactivators is often mediated through one of its activation domains. Many NRs have at least two activation domains, the ligand-independent activation function (AF)-1, which resides in the N-terminal domain, and the ligand-dependent AF-2, which is localized in the C-terminal domain. In this review, we summarize and discuss current knowledge regarding the molecular mechanisms of AF-1- and AF-2-mediated gene activation, focusing on AF-1 and AF-2 conformation and coactivator binding.

scholarly journals Review of the in Vivo Functions of the p160 Steroid Receptor Coactivator Family

2003 ◽  
Vol 17 (9) ◽  
pp. 1681-1692 ◽  
Author(s):  
Jianming Xu ◽  
Qingtian Li
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Steroid Receptor ◽  
Molecular Structures ◽  
Endocrine Regulation ◽  
Steroid Receptor Coactivator

Abstract The p160 steroid receptor coactivator (SRC) gene family contains three homologous members, which serve as transcriptional coactivators for nuclear receptors and certain other transcription factors. These coactivators interact with ligand-bound nuclear receptors to recruit histone acetyltransferases and methyltransferases to specific enhancer/promotor regions, which facilitates chromatin remodeling, assembly of general transcription factors, and transcription of target genes. This minireview summarizes our current knowledge about the molecular structures, molecular mechanisms, temporal and spatial expression patterns, and biological functions of the SRC family. In particular, this article highlights the roles of SRC-1 (NCoA-1), SRC-2 (GRIP1, TIF2, or NCoA-2) and SRC-3 (p/CIP, RAC3, ACTR, AIB1, or TRAM-1) in development, organ function, endocrine regulation, and nuclear receptor function, which are defined by characterization of the genetically manipulated animal models. Furthermore, this article also reviews our current understanding of the role of SRC-3 in breast cancer and discusses possible mechanisms for functional specificity and redundancy among SRC family members.

scholarly journals Stepwise Recruitment of Components of the Preinitiation Complex by Upstream Activators In Vivo

1998 ◽  
Vol 18 (5) ◽  
pp. 2876-2883 ◽  
Author(s):  
Song He ◽  
Steven Jay Weintraub
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Mechanism Of Action ◽  
Transcriptional Activation ◽  
Tata Binding Protein ◽  
Preinitiation Complex ◽  
Functional Assays ◽  
Rna Polymerase Ii Holoenzyme

ABSTRACT Recently, it was found that if either the TATA binding protein or RNA polymerase II holoenzyme is artificially tethered to a promoter, transcription is activated. This finding provided presumptive evidence that upstream activating proteins function by recruiting components of the preinitiation complex (PIC) to the promoter. To date, however, there have been no studies demonstrating that upstream factors actually recruit components of the PIC to the promoter in vivo. Therefore, we have studied the mechanism of action of two disparate transactivating domains. We present a series of in vivo functional assays that demonstrate that each of these proteins targets different components of the PIC for recruitment. We show that, by targeting different components of the PIC for recruitment, these activating domains can cooperate with each other to activate transcription synergistically and that, even within one protein, two different activating subdomains can activate transcription synergistically by cooperating to recruit different components of the PIC. Finally, considering our work together with previous studies, we propose that certain transcription factors both recruit components of the PIC and facilitate steps in transcriptional activation that occur subsequent to recruitment.

scholarly journals Regulation of Thermotolerance by Stress-Induced Transcription Factors in Saccharomyces cerevisiae

2008 ◽  
Vol 7 (5) ◽  
pp. 783-790 ◽  
Author(s):  
Noritaka Yamamoto ◽  
Yuka Maeda ◽  
Aya Ikeda ◽  
Hiroshi Sakurai
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcription Factors ◽  
High Temperature ◽  
Heat Shock ◽  
Cell Growth ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Recovery Period ◽  
Before And After

ABSTRACT The heat shock transcription factor Hsf1 and the general stress transcription factors Msn2 and Msn4 (Msn2/4) are major regulators of the heat shock response in Saccharomyces cerevisiae. Here, we show that transcriptional activation of their target genes, including HSP104, an antistress chaperone gene, is obligatory for thermotolerance. Although Hsf1 activity might be necessary before the exposure of cells to high temperature, severe heat shock induced the binding of hyperphosphorylated Hsf1 to its target promoters. However, promoter-bound, phosphorylated Hsf1 was inactive for transcription because RNA polymerase II was inactive at high temperatures. Rather, our results suggest that Hsf1 activates the transcription of most of its target genes during the recovery period following severe heat shock. This delayed upregulation by Hsf1, which would be induced by misfolded proteins that accumulate in severely heat-shocked cells, is required for the resumption of normal cell growth. In contrast, the factors Msn2/4 were not involved in the delayed upregulation of genes and were dispensable for cell growth during the recovery period, suggesting that they play a role before the exposure to high temperature. These results show that Hsf1 and Msn2/4 act differentially before and after exposure to extreme temperatures to ensure cell survival and growth.

scholarly journals NRIF3 Is a Novel Coactivator Mediating Functional Specificity of Nuclear Hormone Receptors

1999 ◽  
Vol 19 (10) ◽  
pp. 7191-7202 ◽  
Author(s):  
Dangsheng Li ◽  
Vandana Desai-Yajnik ◽  
Eric Lo ◽  
Matthieu Schapira ◽  
Ruben Abagyan ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Specific Interaction ◽  
Minor Role ◽  
Receptor Specificity ◽  
Terminal Domain

ABSTRACT Many nuclear receptors are capable of recognizing similar DNA elements. The molecular event(s) underlying the functional specificities of these receptors (in regulating the expression of their native target genes) is a very important issue that remains poorly understood. Here we report the cloning and analysis of a novel nuclear receptor coactivator (designated NRIF3) that exhibits a distinct receptor specificity. Fluorescence microscopy shows that NRIF3 localizes to the cell nucleus. The yeast two-hybrid and/or in vitro binding assays indicated that NRIF3 specifically interacts with the thyroid hormone receptor (TR) and retinoid X receptor (RXR) in a ligand-dependent fashion but does not bind to the retinoic acid receptor, vitamin D receptor, progesterone receptor, glucocorticoid receptor, or estrogen receptor. Functional experiments showed that NRIF3 significantly potentiates TR- and RXR-mediated transactivation in vivo but has little effect on other examined nuclear receptors. Domain and mutagenesis analyses indicated that a novel C-terminal domain in NRIF3 plays an essential role in its specific interaction with liganded TR and RXR while the N-terminal LXXLL motif plays a minor role in allowing optimum interaction. Computer modeling and subsequent experimental analysis suggested that the C-terminal domain of NRIF3 directly mediates interaction with liganded receptors through an LXXIL (a variant of the canonical LXXLL) module while the other part of the NRIF3 protein may still play a role in conferring its receptor specificity. Identification of a coactivator with such a unique receptor specificity may provide new insight into the molecular mechanism(s) of receptor-mediated transcriptional activation as well as the functional specificities of nuclear receptors.

scholarly journals A highly conserved domain of RNA polymerase II shares a functional element with acidic activation domains of upstream transcription factors

1994 ◽  
Vol 14 (11) ◽  
pp. 7507-7516
Author(s):  
H Xiao ◽  
J D Friesen ◽  
J T Lis
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Normal Function ◽  
Yeast Saccharomyces Cerevisiae ◽  
Activation Domains ◽  
Acidic Domain ◽  
General Transcription Factors ◽  
Derivatives Of

We report here that the largest subunit of yeast RNA polymerase II contains an acidic domain that is similar to acidic activators of transcription. This domain includes the highly conserved homology box H. A hybrid protein containing this acidic domain fused to the DNA-binding domain of GAL4 is a potent activator of transcription in the yeast Saccharomyces cerevisiae. Interestingly, mutations that reduce the upstream activating activity of this acidic domain also abolish the normal function of RNA polymerase II. Such functional defects can be rescued by the acidic activation domains of VP16 and GAL4 when inserted into the mutant derivatives of RNA polymerase II. We further show that this acidic domain of RNA polymerase II interacts directly with two general transcription factors, the TATA-binding protein and TFIIB, and that the acidic activation domain of VP16 can compete specifically with the acidic domain of the RNA polymerase for these interactions. We discuss the implications of this finding for the mechanisms of transcriptional activation in eucaryotes.

scholarly journals A highly conserved domain of RNA polymerase II shares a functional element with acidic activation domains of upstream transcription factors.

1994 ◽  
Vol 14 (11) ◽  
pp. 7507-7516 ◽  
Author(s):  
H Xiao ◽  
J D Friesen ◽  
J T Lis
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Normal Function ◽  
Yeast Saccharomyces Cerevisiae ◽  
Activation Domains ◽  
Acidic Domain ◽  
General Transcription Factors ◽  
Derivatives Of

We report here that the largest subunit of yeast RNA polymerase II contains an acidic domain that is similar to acidic activators of transcription. This domain includes the highly conserved homology box H. A hybrid protein containing this acidic domain fused to the DNA-binding domain of GAL4 is a potent activator of transcription in the yeast Saccharomyces cerevisiae. Interestingly, mutations that reduce the upstream activating activity of this acidic domain also abolish the normal function of RNA polymerase II. Such functional defects can be rescued by the acidic activation domains of VP16 and GAL4 when inserted into the mutant derivatives of RNA polymerase II. We further show that this acidic domain of RNA polymerase II interacts directly with two general transcription factors, the TATA-binding protein and TFIIB, and that the acidic activation domain of VP16 can compete specifically with the acidic domain of the RNA polymerase for these interactions. We discuss the implications of this finding for the mechanisms of transcriptional activation in eucaryotes.

Epigenetic control of hematopoiesis: the PU.1 chromatin connection

2014 ◽  
Vol 395 (11) ◽  
pp. 1265-1274 ◽  
Author(s):  
Boet van Riel ◽  
Frank Rosenbauer
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Dna Methyltransferases ◽  
Chromatin Remodelers ◽  
Cell Lineages ◽  
Protein Partners ◽  
Genome Wide

Abstract Purine-rich box1 (PU.1) is a transcription factor that not only has a key role in the development of most hematopoietic cell lineages but also in the suppression of leukemia. To exert these functions, PU.1 can cross-talk with multiple different proteins by forming complexes in order to activate or repress transcription. Among its protein partners are chromatin remodelers, DNA methyltransferases, and a number of other transcription factors with important roles in hematopoiesis. While a great deal of knowledge has been acquired about PU.1 function over the years, it was the development of novel genome-wide technologies, which boosted our understanding of how PU.1 acts on the chromatin to drive its repertoire of target genes. This review summarizes current knowledge and ideas of molecular mechanisms by which PU.1 controls hematopoiesis and suppresses leukemia.

scholarly journals A common intermediary factor (p52/54) recognizing "acidic blob"-type domains is required for transcriptional activation by the Jun proteins.

1992 ◽  
Vol 12 (12) ◽  
pp. 5508-5515 ◽  
Author(s):  
T Oehler ◽  
P Angel
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Serum Response Factor ◽  
Limiting Factor ◽  
Regulation Of Transcription ◽  
Physical Interaction ◽  
Main Component

The ability of the c-Jun protein, the main component of the transcription factor AP1, to interact directly or indirectly with the RNA polymerase II-initiation complex to activate transcription was investigated by in vivo transcription interference ("squelching") experiments. Coexpression of a Jun mutant lacking its DNA binding domain strongly represses the activity of wild-type c-Jun. Repression depends on the presence of the transactivation domains (TADs), suggesting that a limiting factor interacting with the TADs is essential to link Jun and the components of the transcriptional machinery. The activity of this intermediary factor(s) is restricted to TADs characterized by an abundance of negatively charged amino acids, as demonstrated by the abilities of the TADs of JunB, GAL4, and VP16 to repress c-Jun activity. Depending on the presence of the TADs of Jun, we found physical interaction between Jun and a cluster of three proteins with molecular masses of 52, 53, and 54 kDa (p52/54). Association between Jun and p52/54 is strongly reduced in the presence of VP16, suggesting that the two proteins compete for binding to p52/54. Transcription factors containing a different type of TAD (e.g., GHF1, estrogen receptor, or serum response factor) fail to inhibit Jun activity, suggesting that these proteins act through a different mechanism. We consider the requirement of Jun to interact with p52/54 utilized by other transcription factors a new mechanism in the regulation of transcription of Jun-dependent target genes.

scholarly journals The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression

2015 ◽  
Vol 36 (3) ◽  
pp. 407-420 ◽  
Author(s):  
Hiroki Sekine ◽  
Keito Okazaki ◽  
Nao Ota ◽  
Hiroki Shima ◽  
Yasutake Katoh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Antioxidant Response ◽  
Wild Type ◽  
Antioxidant Genes ◽  
Antioxidant Gene Expression

The KEAP1-NRF2 system plays a central role in cytoprotection. NRF2 is stabilized in response to electrophiles and activates transcription of antioxidant genes. Although robust induction of NRF2 target genes confers resistance to oxidative insults, how NRF2 triggers transcriptional activation after binding to DNA has not been elucidated. To decipher the molecular mechanisms underlying NRF2-dependent transcriptional activation, we purified the NRF2 nuclear protein complex and identified the Mediator subunits as NRF2 cofactors. Among them, MED16 directly associated with NRF2. Disruption ofMed16significantly attenuated the electrophile-induced expression of NRF2 target genes but did not affect hypoxia-induced gene expression, suggesting a specific requirement for MED16 in NRF2-dependent transcription. Importantly, we found that 75% of NRF2-activated genes exhibited blunted inductions by electrophiles inMed16-deficient cells compared to wild-type cells, which strongly argues that MED16 is a major contributor supporting NRF2-dependent transcriptional activation. NRF2-dependent phosphorylation of the RNA polymerase II C-terminal domain was absent inMed16-deficient cells, suggesting that MED16 serves as a conduit to transmit NRF2-activating signals to RNA polymerase II. MED16 indeed turned out to be essential for cytoprotection against oxidative insults. Thus, the KEAP1-NRF2-MED16 axis has emerged as a new regulatory pathway mediating the antioxidant response through the robust activation of NRF2 target genes.

A common intermediary factor (p52/54) recognizing "acidic blob"-type domains is required for transcriptional activation by the Jun proteins

1992 ◽  
Vol 12 (12) ◽  
pp. 5508-5515
Author(s):  
T Oehler ◽  
P Angel
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Serum Response Factor ◽  
Limiting Factor ◽  
Regulation Of Transcription ◽  
Physical Interaction ◽  
Main Component

The ability of the c-Jun protein, the main component of the transcription factor AP1, to interact directly or indirectly with the RNA polymerase II-initiation complex to activate transcription was investigated by in vivo transcription interference ("squelching") experiments. Coexpression of a Jun mutant lacking its DNA binding domain strongly represses the activity of wild-type c-Jun. Repression depends on the presence of the transactivation domains (TADs), suggesting that a limiting factor interacting with the TADs is essential to link Jun and the components of the transcriptional machinery. The activity of this intermediary factor(s) is restricted to TADs characterized by an abundance of negatively charged amino acids, as demonstrated by the abilities of the TADs of JunB, GAL4, and VP16 to repress c-Jun activity. Depending on the presence of the TADs of Jun, we found physical interaction between Jun and a cluster of three proteins with molecular masses of 52, 53, and 54 kDa (p52/54). Association between Jun and p52/54 is strongly reduced in the presence of VP16, suggesting that the two proteins compete for binding to p52/54. Transcription factors containing a different type of TAD (e.g., GHF1, estrogen receptor, or serum response factor) fail to inhibit Jun activity, suggesting that these proteins act through a different mechanism. We consider the requirement of Jun to interact with p52/54 utilized by other transcription factors a new mechanism in the regulation of transcription of Jun-dependent target genes.

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