Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinoma

Wang, Ranran; Cao, Xing Jun; Kulej, Katarzyna; Liu, Wei; Ma, Tongcui; MacDonald, Margo; Chiang, Cheng Ming; García, Benjamin A.; You, Jianxin

doi:10.1073/pnas.1703071114

Cited by 49 publications

(70 citation statements)

References 73 publications

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“…Phosphorylation of Brd4 is critical for its activation and also mediates alterations in its interactome. Brd4 hyperphosphorylation correlates with its oncogenic potential and increased phosphorylation levels lead to development of BET inhibitor resistance in certain types of cancer (46, 47). At present, casein kinase 2 (CK2) is the only protein kinase demonstrated to directly phosphorylate Brd4, although others have been shown to regulate Brd4 activity (35, 46, 48).…”

Section: Discussionmentioning

confidence: 99%

“…Brd4 hyperphosphorylation correlates with its oncogenic potential and increased phosphorylation levels lead to development of BET inhibitor resistance in certain types of cancer (46, 47). At present, casein kinase 2 (CK2) is the only protein kinase demonstrated to directly phosphorylate Brd4, although others have been shown to regulate Brd4 activity (35, 46, 48). CK2 phosphorylation sites reside within the PDID domain, where phosphorylation results in a conformational change that unmasks the second bromodomain and enables interactions with acetyl-lysine residues (35).…”

Section: Discussionmentioning

confidence: 99%

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Differential activation of P-TEFb complexes in the development of cardiomyocyte hypertrophy following activation of distinct GPCRs

Martin¹,

Sun²,

MacKinnon³

et al. 2020

Preprint

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AbstractPathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and is accompanied by large-scale changes in cardiomyocyte gene expression. These transcriptional changes require activity of positive transcription elongation factor b (P-TEFb), which is recruited to target genes by the bromodomain protein Brd4 or the Super Elongation Complex (SEC). Here we describe GPCR-specific regulation of these P-TEFb complexes and a novel mechanism for activating Brd4 in primary neonatal rat cardiomyocytes. The SEC was required for the hypertrophic response downstream of either the α1-adrenergic receptor (α1-AR) or the endothelin receptor (ETR). In contrast, Brd4 inhibition selectively impaired the α1-AR response. This was corroborated by the finding that activation of α1-AR, but not ETR, increased Brd4 occupancy at promoters and super enhancers of hypertrophic genes. Transcriptome analysis demonstrated that activation of both receptors initiated similar gene expression programs, but that Brd4 inhibition attenuated hypertrophic genes more robustly following α1-AR activation. Finally, we show that protein kinase A (PKA) is required for α1-AR stimulation of Brd4 chromatin occupancy. The differential role of the Brd4/P-TEFb complex in response to distinct GPCR pathways has potential clinical implications as therapies targeting this complex are currently being explored for heart failure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential activation of P-TEFb complexes in the development of cardiomyocyte hypertrophy following activation of distinct GPCRs

Martin¹,

Sun²,

MacKinnon³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The BRD4 gene is the best‐characterized member of the bromo‐ and extra‐terminal domain family of proteins and plays an important role in cellular growth control, cell cycle progression, and cancer development (Najafova et al, ; Wang et al, ). Houzelstein and coworkers (), studding a mouse model of the Brd4 gene, showed that the heterozygous mice displayed pre and postnatal growth defects associated with a reduced cell proliferation rate.…”

Section: Discussionmentioning

confidence: 99%

A recognizable phenotype related to 19p13.12 microdeletion

Souza

Sgardioli

Vieira

2018

American J of Med Genetics Pt A

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Submicroscopic deletions in chromosome 19 have been rarely reported. We reported a male patient presenting with neurodevelopmental delay and facial dysmorphisms with a de novo 19p13.11p13.12 deletion of approximately 1.4 Mb. To date, there are seven cases with deletions overlapping the 19p13.11-p13.12 region described in the literature. A region of 800 kb for branchial arch defects in the proximal region of 19p13.12, and another minimal critical region of 305 kb for hypertrichosis, synophrys, and protruding front teeth have been proposed previously. We suggest that the shortest region of overlap could be refined to an approximately 53 kb region shared within all patients, encompassing part of BRD4 and AKAP8L genes and the AKAP8 gene. Based on the genotype-phenotype correlation of the present case and cases with overlapping deletions described in the literature, it was possible to recognize a consistent phenotype characterized by microcephaly, ear abnormalities, rounded face, synophrys, arched or upwardly angulated eyebrows, short nose, anteverted nares, prominent cheeks, teeth abnormalities, and developmental delay.

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“…Une autre preuve du rôle de Brd4 dans la tumorigenèse est apparue à la suite de la découverte de formes de fusion entre Brd4 et NUT (nuclear protein in testis) dans la majorité des carcinomes de la ligne médiane 5 . Ces protéines de fusion assurent un remodelage de la chromatine et de la transcription nécessitant leur phosphorylation par cdk9 [42]. D'autres protéines de fusion responsables de transformation cellulaire et retrouvées dans environ 5 % des leucémies aiguës, aboutissent à la formation de complexes impliquant P-TEFb, induisant une transcription aberrante [43].…”

Section: Les Risques De Cibler Des Protéines Pléiotropiquesunclassified

P-TEFb et Brd4

et al. 2018

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Most cell physiology events are dictated by the integration of perceived signals and the elaboration by cells of adapted answers via the execution of proper transcriptional programs. In order to ensure an optimal control of these answers, many regulation mechanisms have been selected throughout the evolution, thus allowing to fine-tune transcript expression. The transcriptional pause and its release by P-TEFb (Positive Transcription Elongation Factor) have been evidenced two decades ago. Since then, the importance of such mechanisms has been highlighted by the association between alterations of this machinery and the appearance of diseases. P-TEFb and Brd4 have thus recently emerged as potential therapeutical targets for cancers and AIDS notably. In this review, we present a brief case history and an up-to-date synthesis of models for transcriptional pause release. We later discuss on the pathophysiological processes associated with this mechanism and clinical trials targeting Brd4 and P-TEFb.

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Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinoma

Cited by 49 publications

References 73 publications

Differential activation of P-TEFb complexes in the development of cardiomyocyte hypertrophy following activation of distinct GPCRs

Differential activation of P-TEFb complexes in the development of cardiomyocyte hypertrophy following activation of distinct GPCRs

A recognizable phenotype related to 19p13.12 microdeletion

P-TEFb et Brd4

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