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Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth.

Small molecule inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of... Full description

Journal Title: The Journal of biological chemistry December 23, 2016, Vol.291(52), pp.26647-26657
Main Author: Niu, Ningning
Other Authors: Shao, Rui , Yan, Guang , Zou, Weiguo
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1083-351X ; DOI: 1083-351X ; DOI: 10.1074/jbc.M116.749697
Link: http://search.proquest.com/docview/1837292015/?pq-origsite=primo
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title: Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth.
format: Article
creator:
  • Niu, Ningning
  • Shao, Rui
  • Yan, Guang
  • Zou, Weiguo
subjects:
  • Animals–Drug Effects
  • Bone Development–Drug Effects
  • Cell Differentiation–Drug Effects
  • Cell Proliferation–Cytology
  • Cells, Cultured–Drug Effects
  • Chondrocytes–Metabolism
  • Chondrogenesis–Drug Effects
  • Collagen Type II–Metabolism
  • Gene Expression Regulation, Neoplastic–Drug Effects
  • Heterocyclic Compounds, 4 or More Rings–Pharmacology
  • Humans–Antagonists & Inhibitors
  • Mice–Genetics
  • Multigene Family–Metabolism
  • Nuclear Proteins–Genetics
  • Promoter Regions, Genetic–Antagonists & Inhibitors
  • Protein-Serine-Threonine Kinases–Genetics
  • RNA-Binding Proteins–Metabolism
  • Small Molecule Libraries–Antagonists & Inhibitors
  • Transcription Factors–Genetics
  • Zebrafish–Metabolism
  • Zebrafish–Pharmacology
  • Zebrafish–Antagonists & Inhibitors
  • Zebrafish–Genetics
  • Zebrafish–Metabolism
  • Zebrafish–Growth & Development
  • Zebrafish–Metabolism
  • Brd3 Protein, Human
  • Brd4 Protein, Human
  • Brdt Protein, Human
  • Col2a1 Protein, Human
  • Collagen Type II
  • Gsk1210151a
  • Heterocyclic Compounds, 4 or More Rings
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Small Molecule Libraries
  • Transcription Factors
  • Brd2 Protein, Human
  • Protein-Serine-Threonine Kinases
  • Bet Inhibitors
  • Col2a1
  • Anticancer Drug
  • Bone
  • Cartilage
  • Chondrocyte
  • Epigenetics
ispartof: The Journal of biological chemistry, December 23, 2016, Vol.291(52), pp.26647-26657
description: Small molecule inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line ATDC5 in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of the chondrocyte. The Col2a1-luciferase ATDC5 system was used for rapidly screening both activators and repressors of human collagen Col2a1 gene expression, and we found that BET bromodomain inhibitors reduce the Col2a1-luciferase. Consistent with the luciferase assay, BET inhibitors decrease the expression of Col2a1 Furthermore, we constructed a zebrafish line in which the enhanced green fluorescent protein (EGFP) expression was driven by col2a1 promoter. The transgenic (col2a1-EGFP) zebrafish line demonstrated that BET inhibitors I-BET151 and (+)-JQ1 may affect EGFP expression in zebrafish. Furthermore, we found that I-BET151 and (+)-JQ1 may affect chondrocyte differentiation in vitro and inhibit zebrafish growth in vivo Mechanistic analysis revealed that BET inhibitors influenced the depletion of RNA polymerase II from the Col2a1 promoter. Collectively, these results suggest that BET bromodomain inhibition may have side effects on skeletal bone structures.
language: eng
source:
identifier: E-ISSN: 1083-351X ; DOI: 1083-351X ; DOI: 10.1074/jbc.M116.749697
fulltext: fulltext
issn:
  • 1083351X
  • 1083-351X
url: Link


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titleBromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth.
creatorNiu, Ningning ; Shao, Rui ; Yan, Guang ; Zou, Weiguo
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subjectAnimals–Drug Effects ; Bone Development–Drug Effects ; Cell Differentiation–Drug Effects ; Cell Proliferation–Cytology ; Cells, Cultured–Drug Effects ; Chondrocytes–Metabolism ; Chondrogenesis–Drug Effects ; Collagen Type II–Metabolism ; Gene Expression Regulation, Neoplastic–Drug Effects ; Heterocyclic Compounds, 4 or More Rings–Pharmacology ; Humans–Antagonists & Inhibitors ; Mice–Genetics ; Multigene Family–Metabolism ; Nuclear Proteins–Genetics ; Promoter Regions, Genetic–Antagonists & Inhibitors ; Protein-Serine-Threonine Kinases–Genetics ; RNA-Binding Proteins–Metabolism ; Small Molecule Libraries–Antagonists & Inhibitors ; Transcription Factors–Genetics ; Zebrafish–Metabolism ; Zebrafish–Pharmacology ; Zebrafish–Antagonists & Inhibitors ; Zebrafish–Genetics ; Zebrafish–Metabolism ; Zebrafish–Growth & Development ; Zebrafish–Metabolism ; Brd3 Protein, Human ; Brd4 Protein, Human ; Brdt Protein, Human ; Col2a1 Protein, Human ; Collagen Type II ; Gsk1210151a ; Heterocyclic Compounds, 4 or More Rings ; Nuclear Proteins ; RNA-Binding Proteins ; Small Molecule Libraries ; Transcription Factors ; Brd2 Protein, Human ; Protein-Serine-Threonine Kinases ; Bet Inhibitors ; Col2a1 ; Anticancer Drug ; Bone ; Cartilage ; Chondrocyte ; Epigenetics
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descriptionSmall molecule inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line ATDC5 in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of the chondrocyte. The Col2a1-luciferase ATDC5 system was used for rapidly screening both activators and repressors of human collagen Col2a1 gene expression, and we found that BET bromodomain inhibitors reduce the Col2a1-luciferase. Consistent with the luciferase assay, BET inhibitors decrease the expression of Col2a1 Furthermore, we constructed a zebrafish line in which the enhanced green fluorescent protein (EGFP) expression was driven by col2a1 promoter. The transgenic (col2a1-EGFP) zebrafish line demonstrated that BET inhibitors I-BET151 and (+)-JQ1 may affect EGFP expression in zebrafish. Furthermore, we found that I-BET151 and (+)-JQ1 may affect chondrocyte differentiation in vitro and inhibit zebrafish growth in vivo Mechanistic analysis revealed that BET inhibitors influenced the depletion of RNA polymerase II from the Col2a1 promoter. Collectively, these results suggest that BET bromodomain inhibition may have side effects on skeletal bone structures.
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7Collagen Type II–Metabolism
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9Heterocyclic Compounds, 4 or More Rings–Pharmacology
10Humans–Antagonists & Inhibitors
11Mice–Genetics
12Multigene Family–Metabolism
13Nuclear Proteins–Genetics
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15Protein-Serine-Threonine Kinases–Genetics
16RNA-Binding Proteins–Metabolism
17Small Molecule Libraries–Antagonists & Inhibitors
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36Protein-Serine-Threonine Kinases
37Bet Inhibitors
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39Anticancer Drug
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titleBromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth.
authorNiu, Ningning ; Shao, Rui ; Yan, Guang ; Zou, Weiguo
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5Chondrocytes–Metabolism
6Chondrogenesis–Drug Effects
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9Heterocyclic Compounds, 4 or More Rings–Pharmacology
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11Mice–Genetics
12Multigene Family–Metabolism
13Nuclear Proteins–Genetics
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15Protein-Serine-Threonine Kinases–Genetics
16RNA-Binding Proteins–Metabolism
17Small Molecule Libraries–Antagonists & Inhibitors
18Transcription Factors–Genetics
19Zebrafish–Metabolism
20Zebrafish–Pharmacology
21Zebrafish–Antagonists & Inhibitors
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