Recruitment of chromatin remodelling factors during gene activation via the glucocorticoid receptor N-terminal domain

2000 ◽  
Vol 28 (4) ◽  
pp. 410-414 ◽  
Author(s):  
A. E. Wallberg ◽  
E. M. Flinn ◽  
J.-Å. Gustafsson ◽  
A. P. H. Wright
Keyword(s):  
Glucocorticoid Receptor ◽  
Protein Complexes ◽  
Gene Activation ◽  
Adaptor Proteins ◽  
Chromatin Remodelling ◽  
Saga Complex ◽  
Activation Domains ◽  
Physical Interactions ◽  
Yeast Mutants

We have shown that yeast mutants with defects in the Ada adaptor proteins are defective in hormone-dependent gene activation by ectopically expressed human glucocorticoid receptor (GR). Others have shown that the Ada2 protein is required for physical interactions between some activation domains and TBP (TATA-binding protein), whereas the Gcn5 (Ada4) protein has a histone acetyltransferase (HAT) activity. Although all HAT enzymes are able to acetylate histone substrates, some also acetylate non-histone proteins. Taken together, these observations suggest that the Ada proteins have the ability to effect different steps in the process of gene activation. It has recently been shown that the Ada proteins are present in two distinct protein complexes, the Ada complex and a larger SAGA complex. Our recent work has focused on determining (1) which of the Ada-containing complexes mediates gene activation by GR, (2) whether the HAT activity encoded by GCN5 is required for GR-dependent gene activation, (3) whether the Ada proteins contribute to GR-mediated activation at the level of chromatin remodelling and (4) how the role of these HAT complexes is integrated with other chromatin remodelling activities during GR-mediated gene activation. Our results suggest a model in which GR recruits the SAGA complex and that this contributes to chromatin remodelling via a mechanism involving the acetylation of histones. Furthermore, recruitment of the SWI/SNF remodelling complex also has a role in GR-mediated activation that is independent of the role of SAGA. These complexes are similar to analogous mammalian complexes and therefore these results are likely to be relevant to the human system.

scholarly journals Role of Acidic and Phosphorylated Residues in Gene Activation by the Glucocorticoid Receptor

1995 ◽  
Vol 270 (29) ◽  
pp. 17535-17540 ◽  
Author(s):  
Tova Almlöf ◽  
Anthony P. H. Wright ◽  
Jan- Gustafsson
Keyword(s):  
Glucocorticoid Receptor ◽  
Gene Activation

scholarly journals The autophagy protein Ambra1 regulates gene expression by supporting novel transcriptional complexes

2020 ◽  
Vol 295 (34) ◽  
pp. 12045-12057
Author(s):  
Christina Schoenherr ◽  
Adam Byron ◽  
Billie Griffith ◽  
Alexander Loftus ◽  
Jimi C. Wills ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Cell Biology ◽  
Protein Complexes ◽  
Transcriptional Regulators ◽  
Adaptor Proteins ◽  
Nuclear Pore ◽  
Biochemical Fractionation

Ambra1 is considered an autophagy and trafficking protein with roles in neurogenesis and cancer cell invasion. Here, we report that Ambra1 also localizes to the nucleus of cancer cells, where it has a novel nuclear scaffolding function that controls gene expression. Using biochemical fractionation and proteomics, we found that Ambra1 binds to multiple classes of proteins in the nucleus, including nuclear pore proteins, adaptor proteins such as FAK and Akap8, chromatin-modifying proteins, and transcriptional regulators like Brg1 and Atf2. We identified biologically important genes, such as Angpt1, Tgfb2, Tgfb3, Itga8, and Itgb7, whose transcription is regulated by Ambra1-scaffolded complexes, likely by altering histone modifications and Atf2 activity. Therefore, in addition to its recognized roles in autophagy and trafficking, Ambra1 scaffolds protein complexes at chromatin, regulating transcriptional signaling in the nucleus. This novel function for Ambra1, and the specific genes impacted, may help to explain the wider role of Ambra1 in cancer cell biology.

scholarly journals GCN5 and ADA Adaptor Proteins Regulate Triiodothyronine/GRIP1 and SRC-1 Coactivator-Dependent Gene Activation by the Human Thyroid Hormone Receptor

2000 ◽  
Vol 14 (5) ◽  
pp. 718-732 ◽  
Author(s):  
Mordecai Anafi ◽  
Yong-Fan Yang ◽  
Nick A. Barlev ◽  
Manjapra V. Govindan ◽  
Shelley L. Berger ◽  
...  
Keyword(s):  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Gene Activation ◽  
Adaptor Proteins ◽  
Human Thyroid ◽  
Saga Complex ◽  
Interacting Protein ◽  
Activation Of Transcription

Abstract We have used yeast genetics and in vitro protein-protein interaction experiments to explore the possibility that GCN5 (general control nonrepressed protein 5) and several other ADA (alteration/deficiency in activation) adaptor proteins of the multimeric SAGA complex can regulate T3/GRIP1 (glucocorticoid receptor interacting protein 1) and SRC-1 (steroid receptor coactivator-1) coactivator-dependent activation of transcription by the human T3 receptor β1 (hTRβ1). Here, we show that in vivo activation of a T3/GRIP1 or SRC-1 coactivator-dependent T3 hormone response element by hTRβ1 is dependent upon the presence of yeast GCN5, ADA2, ADA1, or ADA3 adaptor proteins and that the histone acetyltransferase (HAT) domains and bromodomain (BrD) of yGCN5 must be intact for maximal activation of transcription. We also observed that hTRβ1 can bind directly to yeast or human GCN5 as well as hADA2, and that the hGCN5387−837 sequence could bind directly to either GRIP1 or SRC-1 coactivator. Importantly, the T3-dependent binding of hTRβ1to hGCN5387−837 could be markedly increased by the presence of GRIP1 or SRC1. Mutagenesis of GRIP1 nuclear receptor (NR) Box II and III LXXLL motifs also substantially decreased both in vivo activation of transcription and in vitro T3-dependent binding of hTRβ1 to hGCN5. Taken together, these experiments support a multistep model of transcriptional initiation wherein the binding of T3 to hTRβ1 initiates the recruitment of p160 coactivators and GCN5 to form a trimeric transcriptional complex that activates target genes through interactions with ADA/SAGA adaptor proteins and nucleosomal histones.

scholarly journals Role of centrosomal adaptor proteins of the TACC family in the regulation of microtubule dynamics during mitotic cell division

2013 ◽  
Vol 394 (11) ◽  
pp. 1411-1423 ◽  
Author(s):  
Harish C. Thakur ◽  
Madhurendra Singh ◽  
Luitgard Nagel-Steger ◽  
Daniel Prumbaum ◽  
Eyad Kalawy Fansa ◽  
...  
Keyword(s):  
Cell Division ◽  
Mitotic Spindle ◽  
Protein Complexes ◽  
Coiled Coil ◽  
Adaptor Proteins ◽  
Mitotic Cell ◽  
Microtubule Dynamics ◽  
Aurora A Kinase ◽  
Spindle Apparatus

Abstract During the mitotic division cycle, cells pass through an extensive microtubule rearrangement process where microtubules forming the mitotic spindle apparatus are dynamically instable. Several centrosomal- and microtubule-associated proteins are involved in the regulation of microtubule dynamics and stability during mitosis. Here, we focus on members of the transforming acidic coiled coil (TACC) family of centrosomal adaptor proteins, in particular TACC3, in which their subcellular localization at the mitotic spindle apparatus is controlled by Aurora-A kinase-mediated phosphorylation. At the effector level, several TACC-binding partners have been identified and characterized in greater detail, in particular, the microtubule polymerase XMAP215/ch-TOG/CKAP5 and clathrin heavy chain (CHC). We summarize the recent progress in the molecular understanding of these TACC3 protein complexes, which are crucial for proper mitotic spindle assembly and dynamics to prevent faulty cell division and aneuploidy. In this regard, the (patho)biological role of TACC3 in development and cancer will be discussed.

scholarly journals The SAGA core module is critical during Drosophila oogenesis and is broadly recruited to promoters

2021 ◽  
Author(s):  
Jelly HM Soffers ◽  
Sergio Garcia-Moreno Alcantara ◽  
Xuanying Li ◽  
Wanqing Shao ◽  
Chrisopher Seidel ◽  
...  
Keyword(s):  
Gene Activation ◽  
Start Site ◽  
Saga Complex ◽  
Drosophila Oogenesis ◽  
The Core ◽  
Core Module ◽  
Entire Complex ◽  
Active Genes ◽  
Coactivator Complex

The Spt/Ada-Gcn5 Acetyltransferase (SAGA) coactivator complex has multiple modules with different enzymatic and non-enzymatic functions. How each module contributes to gene activation in specific biological contexts is not well understood. Here we analyzed the role of the non-enzymatic core module during Drosophila oogenesis. We show that depletion of several SAGA-specific subunits belonging to the core module blocked egg chamber development during mid-oogenesis stages, resulting in stronger phenotypes than those obtained after depletion of SAGA’s histone acetyltransferase module or deubiquitination module. These results, as well as additional genetic analyses pointing to an interaction with TBP, suggested a differential role of SAGA modules at different promoter types. However, SAGA subunits co-occupied all promoter types of active genes in ChIP-seq and ChIP-nexus experiments. Thus, the SAGA complex appears to occupy promoters in its entirety, consistent with the strong biochemical integrity of the complex. The high-resolution genomic binding profiles are congruent with SAGA recruitment by activators upstream of the start site, and retention on chromatin by interactions with modified histones downstream of the start site. The stronger genetic requirement of the core module during oogenesis may therefore be explained through its interaction with TBP or its role in recruiting the enzymatic modules to the promoter. We propose the handyman principle, which posits that a distinct genetic requirement for specific components may conceal the fact that the entire complex is physically present.

scholarly journals A novel transcriptional signalling pathway mediated by the trafficking protein Ambra1 via scaffolding Atf2 complexes

2020 ◽  
Author(s):  
Christina Schoenherr ◽  
Adam Byron ◽  
Margaret C Frame
Keyword(s):  
Cell Invasion ◽  
Protein Complexes ◽  
Transcriptional Regulators ◽  
Adaptor Proteins ◽  
Nuclear Pore ◽  
Cancer Cell Invasion ◽  
Core Component ◽  
Expression Of Genes ◽  
Chromatin Modifiers

ABSTRACTPreviously, we reported that Ambra1 is a core component of a cytoplasmic trafficking network, acting as a spatial rheostat to control active Src and FAK levels in addition to its critical roles in autophagy during neurogenesis. Here we identify a novel nuclear scaffolding function for Ambra1 that controls gene expression. Ambra1 binds to nuclear pore proteins, to other adaptor proteins like FAK and Akap8 in the nucleus, as well as to chromatin modifiers and transcriptional regulators such as Brg1, Cdk9 and the cAMP-regulated transcription factor Atf2. Ambra1 contributes to their association with chromatin and we identified genes whose transcription is regulated by Ambra1 complexes, likely via histone modifications and phospho-Atf2-dependent transcription. Therefore, Ambra1 scaffolds protein complexes at chromatin, regulating transcriptional signalling in the nucleus; in particular, it recruits chromatin modifiers and transcriptional regulators to control expression of genes such as angpt1, tgfb2, tgfb3, itga8 and itgb7 that likely contribute to the role of Ambra1 in cancer cell invasion.

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