Association of bromodomain BET proteins with chromatin requires dimerization through the conserved motif B

García-Gutiérrez, Pablo; Mundi, María; García‐Domínguez, Mario

doi:10.1242/jcs.105841

Cited by 54 publications

(83 citation statements)

References 52 publications

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“…Besides being expressed in neural progenitors, Brd2 is also detected in differentiating neurons of the mantle layer in the developing spinal cord . It has been reported that Brd2 stimulates cell cycle progression (Sinha et al, 2005), and in fact, we have shown that overexpressing Brd2 impairs neuronal differentiation, as it results in elevated expression levels of cyclin D1 and A2 (Garcia-Gutierrez et al, 2012). Thus, the prominent role Brd2 displays during cell proliferation raises the question about its presence in differentiating neurons.…”

Section: Introductionmentioning

confidence: 77%

“…Interestingly, some BET members have been additionally associated with cell differentiation. In this regard, the family member bromodomain-containing protein 2 (Brd2), besides interacting with the transcription factor E2F and controlling expression of cyclin A2 and D1 in proliferating cells (Belkina et al, 2014;Denis et al, 2000;Garcia-Gutierrez et al, 2012;LeRoy et al, 2008;Sinha et al, 2005), is expressed in differentiating neurons , which might be linked to the neural tube closure defects observed in Brd2-knockout mouse embryos and to the association of mutations in the BRD2 locus with human juvenile myoclonic epilepsy (Gyuris et al, 2009;Shang et al, 2009;Velíšek et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to most proteins, including other bromodomain-containing proteins, some of the BET family members have the ability to remain attached to the chromosomes during mitosis (Dey et al, 2003), suggesting they have an epigenetic function. Although binding of BET proteins to the chromatin depends on the integrity of the bromodomains (Kanno et al, 2004), we have recently reported that dimerization through motif B is also required (Garcia-Gutierrez et al, 2012). Knockout mice of BET family members have highlighted the relevance of these proteins for development and survival.…”

Section: Introductionmentioning

confidence: 99%

“…To reconcile these observations and to better understand Brd2 function we have looked for Brd2-interacting proteins. From a previous two-hybrid screening (Garcia-Gutierrez et al, 2012), we identified pleiotrophin (Ptn) as a Brd2-interacting protein, and chose to study it because it is expressed in P19 cells following induction of neuronal differentiation (Brunet-de Carvalho et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

García-Gutiérrez¹,

Juárez-Vicente²,

Wolgemuth³

et al. 2014

Journal of Cell Science

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Bromodomain-containing protein 2 (Brd2) is a BET family chromatin adaptor required for expression of cell-cycle-associated genes and therefore involved in cell cycle progression. Brd2 is expressed in proliferating neuronal progenitors, displays cell-cycle-stimulating activity and, when overexpressed, impairs neuronal differentiation. Paradoxically, Brd2 is also detected in differentiating neurons. To shed light on the role of Brd2 in the transition from cell proliferation to differentiation, we had previously looked for proteins that interacted with Brd2 upon induction of neuronal differentiation. Surprisingly, we identified the growth factor pleiotrophin (Ptn). Here, we show that Ptn antagonized the cell-cycle-stimulating activity associated with Brd2, thus enhancing induced neuronal differentiation. Moreover, Ptn knockdown reduced neuronal differentiation. We analyzed Ptnmediated antagonism of Brd2 in a cell differentiation model and in two embryonic processes associated with the neural tube: spinal cord neurogenesis and neural crest migration. Finally, we investigated the mechanisms of Ptn-mediated antagonism and determined that Ptn destabilizes the association of Brd2 with chromatin. Thus, Ptnmediated Brd2 antagonism emerges as a modulation system accounting for the balance between cell proliferation and differentiation in the vertebrate nervous system.

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Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

García-Gutiérrez¹,

Juárez-Vicente²,

Wolgemuth³

et al. 2014

Journal of Cell Science

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“…It has recently been reported that the motif B is required for association to chromosomes and for homo-and hetero-dimerization between BET proteins. 21) The main function of motif B may not be nuclear retention. It is also possible that there are other domains that serve as a nuclear localization signal or a nuclear export signal.…”

Section: Resultsmentioning

confidence: 99%

The Conserved 12-Amino Acid Stretch in the Inter-Bromodomain Region of BET Family Proteins Functions as a Nuclear Localization Signal

Fukazawa

Masumi

2012

Biological & Pharmaceutical Bulletin

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The bromodomain and extraterminal (BET) family is a group of chromatin-binding proteins characterized by two bromodomains, an extraterminal (ET) domain, and several other conserved regions of unknown function. In humans, the BET family consists of four members, BRD2, BRD3, BRD4 and BRDT, that all normally localize to the nucleus. We identified a 12-amino acid stretch in the inter-bromodomain region that is perfectly conserved among the BET family members. We deleted these residues and expressed the mutant proteins in HEK293T cells to investigate the function of this motif. We found that the deletion of this motif alters the localization of BET proteins. Mutated BRD3 and BRD4 were excluded from the nucleus, and BRDT was found to be diffused throughout the nucleus and cytoplasm. Although the mutant BRD2 remained predominantly in the nucleus, a punctate distribution was also observed in the cytosol. It has been reported that a conserved motif between the second bromodomain and the ET domain serves as a nuclear localization signal for BRD2. Nevertheless, BET mutants lacking the reported nuclear localization signal motif but retaining the 12-amino acid stretch resided in the nucleus. Furthermore, these mutants were diffused throughout the cytoplasm when the 12 residues were removed. These results indicate that the conserved amino acid stretch in the inter-bromodomain region of the BET family functions as a nuclear localization signal. Key words bromodomain; BET family; epigeneticsBromodomains are protein modules of approximately 110 amino acids that interact with acetylated lysine residues and play vital roles in the reading of epigenetic marks on histone tails.1) The bromodomain and extraterminal (BET) family is a subgroup of bromodomain-containing proteins featuring two N-terminal bromodomains and a C-terminal ET domain (Fig. 1). The human BET family of nuclear proteins consists of four members (BRD2, BRD3, BRD4 and BRDT) that have been implicated in various biological processes.BRD4 binds directly to positive transcription elongation factor b (p-TEFb), a complex of cyclin-dependent kinase (CDK) 9 and cyclin T that phosphorylates the RNA Note * To whom correspondence should be addressed. e-mail: fukazawa@nih.go.jp BDI-BDII mutants span the two bromodomains and the sequences in between and lack the other regions. BRD4/del BDI&II is a construct with deletions of both bromodomains. BRD4/intBD encodes a 188-amino acid segment between the two bromodomains.The authors declare no conflict of interest.

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Bromodomains and Their Pharmacological Inhibitors

et al. 2014

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Over 60 bromodomains belonging to proteins with very different functions have been identified in humans. Several of them interact with acetylated lysine residues, leading to the recruitment and stabilization of protein complexes. The bromodomain and extra-terminal domain (BET) proteins contain tandem bromodomains which bind to acetylated histones and are thereby implicated in a number of DNA-centered processes, including the regulation of gene expression. The recent identification of inhibitors of BET and non-BET bromodomains is one of the few examples in which effective blockade of a protein-protein interaction can be achieved with a small molecule. This has led to major strides in the understanding of the function of bromodomain-containing proteins and their involvement in diseases such as cancer and inflammation. Indeed, BET bromodomain inhibitors are now being clinically evaluated for the treatment of hematological tumors and have also been tested in clinical trials for the relatively rare BRD-NUT midline carcinoma. This review gives an overview of the newest developments in the field, with a focus on the biology of selected bromodomain proteins on the one hand, and on reported pharmacological inhibitors on the other, including recent examples from the patent literature.

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Association of bromodomain BET proteins with chromatin requires dimerization through the conserved motif B

Cited by 54 publications

References 52 publications

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

The Conserved 12-Amino Acid Stretch in the Inter-Bromodomain Region of BET Family Proteins Functions as a Nuclear Localization Signal

Bromodomains and Their Pharmacological Inhibitors

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