The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation
Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Ricardo Komotar [verfasserIn] |
|---|
| Format: |
Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2015 |
|---|
| Rechteinformationen: |
Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences |
|---|
| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 112(2015), 27, Seite 8326-8331 |
|---|---|
| Übergeordnetes Werk: |
volume:112 ; year:2015 ; number:27 ; pages:8326-8331 |
| Links: |
|---|
| DOI / URN: |
10.1073/pnas.1424220112 |
|---|
| Katalog-ID: |
OLC1970275138 |
|---|
| LEADER | 01000caa a2200265 4500 | ||
|---|---|---|---|
| 001 | OLC1970275138 | ||
| 003 | DE-627 | ||
| 005 | 20230714175929.0 | ||
| 007 | tu | ||
| 008 | 160211s2015 xx ||||| 00| ||eng c | ||
| 024 | 7 | |a 10.1073/pnas.1424220112 |2 doi | |
| 028 | 5 | 2 | |a PQ20160211 |
| 035 | |a (DE-627)OLC1970275138 | ||
| 035 | |a (DE-599)GBVOLC1970275138 | ||
| 035 | |a (PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83 | ||
| 035 | |a (KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | 4 | |a 500 |q DNB |
| 082 | 0 | 4 | |a 570 |q AVZ |
| 084 | |a LING |2 fid | ||
| 084 | |a BIODIV |2 fid | ||
| 100 | 0 | |a Ricardo Komotar |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation |
| 264 | 1 | |c 2015 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 520 | |a Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. | ||
| 540 | |a Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences | ||
| 650 | 4 | |a Cell Proliferation - genetics | |
| 650 | 4 | |a Heterocyclic Compounds with 4 or More Rings - pharmacology | |
| 650 | 4 | |a Nuclear Proteins - metabolism | |
| 650 | 4 | |a Promoter Regions, Genetic - genetics | |
| 650 | 4 | |a RNA, Long Noncoding - genetics | |
| 650 | 4 | |a Nuclear Proteins - antagonists & inhibitors | |
| 650 | 4 | |a Brain Neoplasms - genetics | |
| 650 | 4 | |a Nuclear Proteins - genetics | |
| 650 | 4 | |a Apoptosis - genetics | |
| 650 | 4 | |a Transcription Factors - antagonists & inhibitors | |
| 650 | 4 | |a Glioblastoma - pathology | |
| 650 | 4 | |a Cell Proliferation - drug effects | |
| 650 | 4 | |a Brain Neoplasms - pathology | |
| 650 | 4 | |a Transcription Factors - genetics | |
| 650 | 4 | |a Gene Expression Regulation, Neoplastic - drug effects | |
| 650 | 4 | |a Xenograft Model Antitumor Assays - methods | |
| 650 | 4 | |a Glioblastoma - metabolism | |
| 650 | 4 | |a Glioblastoma - genetics | |
| 650 | 4 | |a Transcription Factors - metabolism | |
| 650 | 4 | |a RNA, Long Noncoding - metabolism | |
| 650 | 4 | |a Brain Neoplasms - metabolism | |
| 650 | 4 | |a Observations | |
| 650 | 4 | |a Binding proteins | |
| 650 | 4 | |a Glioblastoma multiforme | |
| 650 | 4 | |a Health aspects | |
| 650 | 4 | |a Genetic aspects | |
| 650 | 4 | |a Epigenetic inheritance | |
| 650 | 4 | |a Gene expression | |
| 650 | 4 | |a Proteins | |
| 650 | 4 | |a Ribonucleic acid--RNA | |
| 650 | 4 | |a Epigenetics | |
| 650 | 4 | |a Brain cancer | |
| 650 | 4 | |a Cell growth | |
| 700 | 0 | |a Amade Bregy |4 oth | |
| 700 | 0 | |a Philipp Kapranov |4 oth | |
| 700 | 0 | |a Clara Penas |4 oth | |
| 700 | 0 | |a Veronica Peschansky |4 oth | |
| 700 | 0 | |a Georges St. Laurent |4 oth | |
| 700 | 0 | |a Claes Wahlestedt |4 oth | |
| 700 | 0 | |a Chiara Pastori |4 oth | |
| 700 | 0 | |a Nagi G. Ayad |4 oth | |
| 700 | 0 | |a Jann N. Sarkaria |4 oth | |
| 700 | 0 | |a Claude-Henry Volmar |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d Washington, DC : NAS, 1877 |g 112(2015), 27, Seite 8326-8331 |w (DE-627)129505269 |w (DE-600)209104-5 |w (DE-576)014909189 |x 0027-8424 |7 nnns |
| 773 | 1 | 8 | |g volume:112 |g year:2015 |g number:27 |g pages:8326-8331 |
| 856 | 4 | 1 | |u http://dx.doi.org/10.1073/pnas.1424220112 |3 Volltext |
| 856 | 4 | 2 | |u http://www.pnas.org/content/112/27/8326.abstract |
| 856 | 4 | 2 | |u http://www.ncbi.nlm.nih.gov/pubmed/26111795 |
| 856 | 4 | 2 | |u http://search.proquest.com/docview/1696036543 |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a SYSFLAG_A | ||
| 912 | |a GBV_OLC | ||
| 912 | |a FID-LING | ||
| 912 | |a FID-BIODIV | ||
| 912 | |a SSG-OLC-PHY | ||
| 912 | |a SSG-OLC-CHE | ||
| 912 | |a SSG-OLC-MAT | ||
| 912 | |a SSG-OLC-FOR | ||
| 912 | |a SSG-OLC-PHA | ||
| 912 | |a SSG-OLC-DE-84 | ||
| 912 | |a SSG-OPC-MAT | ||
| 912 | |a SSG-OPC-FOR | ||
| 912 | |a GBV_ILN_40 | ||
| 912 | |a GBV_ILN_59 | ||
| 951 | |a AR | ||
| 952 | |d 112 |j 2015 |e 27 |h 8326-8331 | ||
| author_variant |
r k rk |
|---|---|
| matchkey_str |
article:00278424:2015----::hboooanrtibdcnrlhtiaogocdnrasetafr |
| hierarchy_sort_str |
2015 |
| publishDate |
2015 |
| allfields |
10.1073/pnas.1424220112 doi PQ20160211 (DE-627)OLC1970275138 (DE-599)GBVOLC1970275138 (PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83 (KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Ricardo Komotar verfasserin aut The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Cell Proliferation - genetics Heterocyclic Compounds with 4 or More Rings - pharmacology Nuclear Proteins - metabolism Promoter Regions, Genetic - genetics RNA, Long Noncoding - genetics Nuclear Proteins - antagonists & inhibitors Brain Neoplasms - genetics Nuclear Proteins - genetics Apoptosis - genetics Transcription Factors - antagonists & inhibitors Glioblastoma - pathology Cell Proliferation - drug effects Brain Neoplasms - pathology Transcription Factors - genetics Gene Expression Regulation, Neoplastic - drug effects Xenograft Model Antitumor Assays - methods Glioblastoma - metabolism Glioblastoma - genetics Transcription Factors - metabolism RNA, Long Noncoding - metabolism Brain Neoplasms - metabolism Observations Binding proteins Glioblastoma multiforme Health aspects Genetic aspects Epigenetic inheritance Gene expression Proteins Ribonucleic acid--RNA Epigenetics Brain cancer Cell growth Amade Bregy oth Philipp Kapranov oth Clara Penas oth Veronica Peschansky oth Georges St. Laurent oth Claes Wahlestedt oth Chiara Pastori oth Nagi G. Ayad oth Jann N. Sarkaria oth Claude-Henry Volmar oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 27, Seite 8326-8331 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:27 pages:8326-8331 http://dx.doi.org/10.1073/pnas.1424220112 Volltext http://www.pnas.org/content/112/27/8326.abstract http://www.ncbi.nlm.nih.gov/pubmed/26111795 http://search.proquest.com/docview/1696036543 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 27 8326-8331 |
| spelling |
10.1073/pnas.1424220112 doi PQ20160211 (DE-627)OLC1970275138 (DE-599)GBVOLC1970275138 (PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83 (KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Ricardo Komotar verfasserin aut The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Cell Proliferation - genetics Heterocyclic Compounds with 4 or More Rings - pharmacology Nuclear Proteins - metabolism Promoter Regions, Genetic - genetics RNA, Long Noncoding - genetics Nuclear Proteins - antagonists & inhibitors Brain Neoplasms - genetics Nuclear Proteins - genetics Apoptosis - genetics Transcription Factors - antagonists & inhibitors Glioblastoma - pathology Cell Proliferation - drug effects Brain Neoplasms - pathology Transcription Factors - genetics Gene Expression Regulation, Neoplastic - drug effects Xenograft Model Antitumor Assays - methods Glioblastoma - metabolism Glioblastoma - genetics Transcription Factors - metabolism RNA, Long Noncoding - metabolism Brain Neoplasms - metabolism Observations Binding proteins Glioblastoma multiforme Health aspects Genetic aspects Epigenetic inheritance Gene expression Proteins Ribonucleic acid--RNA Epigenetics Brain cancer Cell growth Amade Bregy oth Philipp Kapranov oth Clara Penas oth Veronica Peschansky oth Georges St. Laurent oth Claes Wahlestedt oth Chiara Pastori oth Nagi G. Ayad oth Jann N. Sarkaria oth Claude-Henry Volmar oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 27, Seite 8326-8331 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:27 pages:8326-8331 http://dx.doi.org/10.1073/pnas.1424220112 Volltext http://www.pnas.org/content/112/27/8326.abstract http://www.ncbi.nlm.nih.gov/pubmed/26111795 http://search.proquest.com/docview/1696036543 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 27 8326-8331 |
| allfields_unstemmed |
10.1073/pnas.1424220112 doi PQ20160211 (DE-627)OLC1970275138 (DE-599)GBVOLC1970275138 (PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83 (KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Ricardo Komotar verfasserin aut The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Cell Proliferation - genetics Heterocyclic Compounds with 4 or More Rings - pharmacology Nuclear Proteins - metabolism Promoter Regions, Genetic - genetics RNA, Long Noncoding - genetics Nuclear Proteins - antagonists & inhibitors Brain Neoplasms - genetics Nuclear Proteins - genetics Apoptosis - genetics Transcription Factors - antagonists & inhibitors Glioblastoma - pathology Cell Proliferation - drug effects Brain Neoplasms - pathology Transcription Factors - genetics Gene Expression Regulation, Neoplastic - drug effects Xenograft Model Antitumor Assays - methods Glioblastoma - metabolism Glioblastoma - genetics Transcription Factors - metabolism RNA, Long Noncoding - metabolism Brain Neoplasms - metabolism Observations Binding proteins Glioblastoma multiforme Health aspects Genetic aspects Epigenetic inheritance Gene expression Proteins Ribonucleic acid--RNA Epigenetics Brain cancer Cell growth Amade Bregy oth Philipp Kapranov oth Clara Penas oth Veronica Peschansky oth Georges St. Laurent oth Claes Wahlestedt oth Chiara Pastori oth Nagi G. Ayad oth Jann N. Sarkaria oth Claude-Henry Volmar oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 27, Seite 8326-8331 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:27 pages:8326-8331 http://dx.doi.org/10.1073/pnas.1424220112 Volltext http://www.pnas.org/content/112/27/8326.abstract http://www.ncbi.nlm.nih.gov/pubmed/26111795 http://search.proquest.com/docview/1696036543 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 27 8326-8331 |
| allfieldsGer |
10.1073/pnas.1424220112 doi PQ20160211 (DE-627)OLC1970275138 (DE-599)GBVOLC1970275138 (PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83 (KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Ricardo Komotar verfasserin aut The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Cell Proliferation - genetics Heterocyclic Compounds with 4 or More Rings - pharmacology Nuclear Proteins - metabolism Promoter Regions, Genetic - genetics RNA, Long Noncoding - genetics Nuclear Proteins - antagonists & inhibitors Brain Neoplasms - genetics Nuclear Proteins - genetics Apoptosis - genetics Transcription Factors - antagonists & inhibitors Glioblastoma - pathology Cell Proliferation - drug effects Brain Neoplasms - pathology Transcription Factors - genetics Gene Expression Regulation, Neoplastic - drug effects Xenograft Model Antitumor Assays - methods Glioblastoma - metabolism Glioblastoma - genetics Transcription Factors - metabolism RNA, Long Noncoding - metabolism Brain Neoplasms - metabolism Observations Binding proteins Glioblastoma multiforme Health aspects Genetic aspects Epigenetic inheritance Gene expression Proteins Ribonucleic acid--RNA Epigenetics Brain cancer Cell growth Amade Bregy oth Philipp Kapranov oth Clara Penas oth Veronica Peschansky oth Georges St. Laurent oth Claes Wahlestedt oth Chiara Pastori oth Nagi G. Ayad oth Jann N. Sarkaria oth Claude-Henry Volmar oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 27, Seite 8326-8331 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:27 pages:8326-8331 http://dx.doi.org/10.1073/pnas.1424220112 Volltext http://www.pnas.org/content/112/27/8326.abstract http://www.ncbi.nlm.nih.gov/pubmed/26111795 http://search.proquest.com/docview/1696036543 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 27 8326-8331 |
| allfieldsSound |
10.1073/pnas.1424220112 doi PQ20160211 (DE-627)OLC1970275138 (DE-599)GBVOLC1970275138 (PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83 (KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Ricardo Komotar verfasserin aut The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Cell Proliferation - genetics Heterocyclic Compounds with 4 or More Rings - pharmacology Nuclear Proteins - metabolism Promoter Regions, Genetic - genetics RNA, Long Noncoding - genetics Nuclear Proteins - antagonists & inhibitors Brain Neoplasms - genetics Nuclear Proteins - genetics Apoptosis - genetics Transcription Factors - antagonists & inhibitors Glioblastoma - pathology Cell Proliferation - drug effects Brain Neoplasms - pathology Transcription Factors - genetics Gene Expression Regulation, Neoplastic - drug effects Xenograft Model Antitumor Assays - methods Glioblastoma - metabolism Glioblastoma - genetics Transcription Factors - metabolism RNA, Long Noncoding - metabolism Brain Neoplasms - metabolism Observations Binding proteins Glioblastoma multiforme Health aspects Genetic aspects Epigenetic inheritance Gene expression Proteins Ribonucleic acid--RNA Epigenetics Brain cancer Cell growth Amade Bregy oth Philipp Kapranov oth Clara Penas oth Veronica Peschansky oth Georges St. Laurent oth Claes Wahlestedt oth Chiara Pastori oth Nagi G. Ayad oth Jann N. Sarkaria oth Claude-Henry Volmar oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 27, Seite 8326-8331 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:27 pages:8326-8331 http://dx.doi.org/10.1073/pnas.1424220112 Volltext http://www.pnas.org/content/112/27/8326.abstract http://www.ncbi.nlm.nih.gov/pubmed/26111795 http://search.proquest.com/docview/1696036543 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 27 8326-8331 |
| language |
English |
| source |
Enthalten in Proceedings of the National Academy of Sciences of the United States of America 112(2015), 27, Seite 8326-8331 volume:112 year:2015 number:27 pages:8326-8331 |
| sourceStr |
Enthalten in Proceedings of the National Academy of Sciences of the United States of America 112(2015), 27, Seite 8326-8331 volume:112 year:2015 number:27 pages:8326-8331 |
| format_phy_str_mv |
Article |
| institution |
findex.gbv.de |
| topic_facet |
Cell Proliferation - genetics Heterocyclic Compounds with 4 or More Rings - pharmacology Nuclear Proteins - metabolism Promoter Regions, Genetic - genetics RNA, Long Noncoding - genetics Nuclear Proteins - antagonists & inhibitors Brain Neoplasms - genetics Nuclear Proteins - genetics Apoptosis - genetics Transcription Factors - antagonists & inhibitors Glioblastoma - pathology Cell Proliferation - drug effects Brain Neoplasms - pathology Transcription Factors - genetics Gene Expression Regulation, Neoplastic - drug effects Xenograft Model Antitumor Assays - methods Glioblastoma - metabolism Glioblastoma - genetics Transcription Factors - metabolism RNA, Long Noncoding - metabolism Brain Neoplasms - metabolism Observations Binding proteins Glioblastoma multiforme Health aspects Genetic aspects Epigenetic inheritance Gene expression Proteins Ribonucleic acid--RNA Epigenetics Brain cancer Cell growth |
| dewey-raw |
500 |
| isfreeaccess_bool |
false |
| container_title |
Proceedings of the National Academy of Sciences of the United States of America |
| authorswithroles_txt_mv |
Ricardo Komotar @@aut@@ Amade Bregy @@oth@@ Philipp Kapranov @@oth@@ Clara Penas @@oth@@ Veronica Peschansky @@oth@@ Georges St. Laurent @@oth@@ Claes Wahlestedt @@oth@@ Chiara Pastori @@oth@@ Nagi G. Ayad @@oth@@ Jann N. Sarkaria @@oth@@ Claude-Henry Volmar @@oth@@ |
| publishDateDaySort_date |
2015-01-01T00:00:00Z |
| hierarchy_top_id |
129505269 |
| dewey-sort |
3500 |
| id |
OLC1970275138 |
| language_de |
englisch |
| fullrecord |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a2200265 4500</leader><controlfield tag="001">OLC1970275138</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230714175929.0</controlfield><controlfield tag="007">tu</controlfield><controlfield tag="008">160211s2015 xx ||||| 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1073/pnas.1424220112</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">PQ20160211</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)OLC1970275138</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)GBVOLC1970275138</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">500</subfield><subfield code="q">DNB</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">570</subfield><subfield code="q">AVZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">LING</subfield><subfield code="2">fid</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">BIODIV</subfield><subfield code="2">fid</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Ricardo Komotar</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="4"><subfield code="a">The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2015</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">ohne Hilfsmittel zu benutzen</subfield><subfield code="b">n</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Band</subfield><subfield code="b">nc</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.</subfield></datafield><datafield tag="540" ind1=" " ind2=" "><subfield code="a">Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cell Proliferation - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Heterocyclic Compounds with 4 or More Rings - pharmacology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Nuclear Proteins - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Promoter Regions, Genetic - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RNA, Long Noncoding - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Nuclear Proteins - antagonists & inhibitors</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brain Neoplasms - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Nuclear Proteins - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Apoptosis - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcription Factors - antagonists & inhibitors</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glioblastoma - pathology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cell Proliferation - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brain Neoplasms - pathology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcription Factors - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Gene Expression Regulation, Neoplastic - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Xenograft Model Antitumor Assays - methods</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glioblastoma - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glioblastoma - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcription Factors - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RNA, Long Noncoding - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brain Neoplasms - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Observations</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Binding proteins</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glioblastoma multiforme</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Health aspects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genetic aspects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Epigenetic inheritance</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Gene expression</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Proteins</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Ribonucleic acid--RNA</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Epigenetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brain cancer</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cell growth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Amade Bregy</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Philipp Kapranov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Clara Penas</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Veronica Peschansky</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Georges St. Laurent</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Claes Wahlestedt</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Chiara Pastori</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Nagi G. Ayad</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jann N. Sarkaria</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Claude-Henry Volmar</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Proceedings of the National Academy of Sciences of the United States of America</subfield><subfield code="d">Washington, DC : NAS, 1877</subfield><subfield code="g">112(2015), 27, Seite 8326-8331</subfield><subfield code="w">(DE-627)129505269</subfield><subfield code="w">(DE-600)209104-5</subfield><subfield code="w">(DE-576)014909189</subfield><subfield code="x">0027-8424</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:112</subfield><subfield code="g">year:2015</subfield><subfield code="g">number:27</subfield><subfield code="g">pages:8326-8331</subfield></datafield><datafield tag="856" ind1="4" ind2="1"><subfield code="u">http://dx.doi.org/10.1073/pnas.1424220112</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://www.pnas.org/content/112/27/8326.abstract</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://www.ncbi.nlm.nih.gov/pubmed/26111795</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://search.proquest.com/docview/1696036543</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_OLC</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-LING</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-BIODIV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHY</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-CHE</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-MAT</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-DE-84</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-MAT</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_59</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">112</subfield><subfield code="j">2015</subfield><subfield code="e">27</subfield><subfield code="h">8326-8331</subfield></datafield></record></collection>
|
| author |
Ricardo Komotar |
| spellingShingle |
Ricardo Komotar ddc 500 ddc 570 fid LING fid BIODIV misc Cell Proliferation - genetics misc Heterocyclic Compounds with 4 or More Rings - pharmacology misc Nuclear Proteins - metabolism misc Promoter Regions, Genetic - genetics misc RNA, Long Noncoding - genetics misc Nuclear Proteins - antagonists & inhibitors misc Brain Neoplasms - genetics misc Nuclear Proteins - genetics misc Apoptosis - genetics misc Transcription Factors - antagonists & inhibitors misc Glioblastoma - pathology misc Cell Proliferation - drug effects misc Brain Neoplasms - pathology misc Transcription Factors - genetics misc Gene Expression Regulation, Neoplastic - drug effects misc Xenograft Model Antitumor Assays - methods misc Glioblastoma - metabolism misc Glioblastoma - genetics misc Transcription Factors - metabolism misc RNA, Long Noncoding - metabolism misc Brain Neoplasms - metabolism misc Observations misc Binding proteins misc Glioblastoma multiforme misc Health aspects misc Genetic aspects misc Epigenetic inheritance misc Gene expression misc Proteins misc Ribonucleic acid--RNA misc Epigenetics misc Brain cancer misc Cell growth The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation |
| authorStr |
Ricardo Komotar |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)129505269 |
| format |
Article |
| dewey-ones |
500 - Natural sciences & mathematics 570 - Life sciences; biology |
| delete_txt_mv |
keep |
| author_role |
aut |
| collection |
OLC |
| remote_str |
false |
| illustrated |
Not Illustrated |
| issn |
0027-8424 |
| topic_title |
500 DNB 570 AVZ LING fid BIODIV fid The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation Cell Proliferation - genetics Heterocyclic Compounds with 4 or More Rings - pharmacology Nuclear Proteins - metabolism Promoter Regions, Genetic - genetics RNA, Long Noncoding - genetics Nuclear Proteins - antagonists & inhibitors Brain Neoplasms - genetics Nuclear Proteins - genetics Apoptosis - genetics Transcription Factors - antagonists & inhibitors Glioblastoma - pathology Cell Proliferation - drug effects Brain Neoplasms - pathology Transcription Factors - genetics Gene Expression Regulation, Neoplastic - drug effects Xenograft Model Antitumor Assays - methods Glioblastoma - metabolism Glioblastoma - genetics Transcription Factors - metabolism RNA, Long Noncoding - metabolism Brain Neoplasms - metabolism Observations Binding proteins Glioblastoma multiforme Health aspects Genetic aspects Epigenetic inheritance Gene expression Proteins Ribonucleic acid--RNA Epigenetics Brain cancer Cell growth |
| topic |
ddc 500 ddc 570 fid LING fid BIODIV misc Cell Proliferation - genetics misc Heterocyclic Compounds with 4 or More Rings - pharmacology misc Nuclear Proteins - metabolism misc Promoter Regions, Genetic - genetics misc RNA, Long Noncoding - genetics misc Nuclear Proteins - antagonists & inhibitors misc Brain Neoplasms - genetics misc Nuclear Proteins - genetics misc Apoptosis - genetics misc Transcription Factors - antagonists & inhibitors misc Glioblastoma - pathology misc Cell Proliferation - drug effects misc Brain Neoplasms - pathology misc Transcription Factors - genetics misc Gene Expression Regulation, Neoplastic - drug effects misc Xenograft Model Antitumor Assays - methods misc Glioblastoma - metabolism misc Glioblastoma - genetics misc Transcription Factors - metabolism misc RNA, Long Noncoding - metabolism misc Brain Neoplasms - metabolism misc Observations misc Binding proteins misc Glioblastoma multiforme misc Health aspects misc Genetic aspects misc Epigenetic inheritance misc Gene expression misc Proteins misc Ribonucleic acid--RNA misc Epigenetics misc Brain cancer misc Cell growth |
| topic_unstemmed |
ddc 500 ddc 570 fid LING fid BIODIV misc Cell Proliferation - genetics misc Heterocyclic Compounds with 4 or More Rings - pharmacology misc Nuclear Proteins - metabolism misc Promoter Regions, Genetic - genetics misc RNA, Long Noncoding - genetics misc Nuclear Proteins - antagonists & inhibitors misc Brain Neoplasms - genetics misc Nuclear Proteins - genetics misc Apoptosis - genetics misc Transcription Factors - antagonists & inhibitors misc Glioblastoma - pathology misc Cell Proliferation - drug effects misc Brain Neoplasms - pathology misc Transcription Factors - genetics misc Gene Expression Regulation, Neoplastic - drug effects misc Xenograft Model Antitumor Assays - methods misc Glioblastoma - metabolism misc Glioblastoma - genetics misc Transcription Factors - metabolism misc RNA, Long Noncoding - metabolism misc Brain Neoplasms - metabolism misc Observations misc Binding proteins misc Glioblastoma multiforme misc Health aspects misc Genetic aspects misc Epigenetic inheritance misc Gene expression misc Proteins misc Ribonucleic acid--RNA misc Epigenetics misc Brain cancer misc Cell growth |
| topic_browse |
ddc 500 ddc 570 fid LING fid BIODIV misc Cell Proliferation - genetics misc Heterocyclic Compounds with 4 or More Rings - pharmacology misc Nuclear Proteins - metabolism misc Promoter Regions, Genetic - genetics misc RNA, Long Noncoding - genetics misc Nuclear Proteins - antagonists & inhibitors misc Brain Neoplasms - genetics misc Nuclear Proteins - genetics misc Apoptosis - genetics misc Transcription Factors - antagonists & inhibitors misc Glioblastoma - pathology misc Cell Proliferation - drug effects misc Brain Neoplasms - pathology misc Transcription Factors - genetics misc Gene Expression Regulation, Neoplastic - drug effects misc Xenograft Model Antitumor Assays - methods misc Glioblastoma - metabolism misc Glioblastoma - genetics misc Transcription Factors - metabolism misc RNA, Long Noncoding - metabolism misc Brain Neoplasms - metabolism misc Observations misc Binding proteins misc Glioblastoma multiforme misc Health aspects misc Genetic aspects misc Epigenetic inheritance misc Gene expression misc Proteins misc Ribonucleic acid--RNA misc Epigenetics misc Brain cancer misc Cell growth |
| format_facet |
Aufsätze Gedruckte Aufsätze |
| format_main_str_mv |
Text Zeitschrift/Artikel |
| carriertype_str_mv |
nc |
| author2_variant |
a b ab p k pk c p cp v p vp g s l gsl c w cw c p cp n g a nga j n s jns c h v chv |
| hierarchy_parent_title |
Proceedings of the National Academy of Sciences of the United States of America |
| hierarchy_parent_id |
129505269 |
| dewey-tens |
500 - Science 570 - Life sciences; biology |
| hierarchy_top_title |
Proceedings of the National Academy of Sciences of the United States of America |
| isfreeaccess_txt |
false |
| familylinks_str_mv |
(DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 |
| title |
The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation |
| ctrlnum |
(DE-627)OLC1970275138 (DE-599)GBVOLC1970275138 (PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83 (KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding |
| title_full |
The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation |
| author_sort |
Ricardo Komotar |
| journal |
Proceedings of the National Academy of Sciences of the United States of America |
| journalStr |
Proceedings of the National Academy of Sciences of the United States of America |
| lang_code |
eng |
| isOA_bool |
false |
| dewey-hundreds |
500 - Science |
| recordtype |
marc |
| publishDateSort |
2015 |
| contenttype_str_mv |
txt |
| container_start_page |
8326 |
| author_browse |
Ricardo Komotar |
| container_volume |
112 |
| class |
500 DNB 570 AVZ LING fid BIODIV fid |
| format_se |
Aufsätze |
| author-letter |
Ricardo Komotar |
| doi_str_mv |
10.1073/pnas.1424220112 |
| dewey-full |
500 570 |
| title_sort |
bromodomain protein brd4 controls hotair, a long noncoding rna essential for glioblastoma proliferation |
| title_auth |
The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation |
| abstract |
Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. |
| abstractGer |
Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. |
| abstract_unstemmed |
Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. |
| collection_details |
GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 |
| container_issue |
27 |
| title_short |
The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation |
| url |
http://dx.doi.org/10.1073/pnas.1424220112 http://www.pnas.org/content/112/27/8326.abstract http://www.ncbi.nlm.nih.gov/pubmed/26111795 http://search.proquest.com/docview/1696036543 |
| remote_bool |
false |
| author2 |
Amade Bregy Philipp Kapranov Clara Penas Veronica Peschansky Georges St. Laurent Claes Wahlestedt Chiara Pastori Nagi G. Ayad Jann N. Sarkaria Claude-Henry Volmar |
| author2Str |
Amade Bregy Philipp Kapranov Clara Penas Veronica Peschansky Georges St. Laurent Claes Wahlestedt Chiara Pastori Nagi G. Ayad Jann N. Sarkaria Claude-Henry Volmar |
| ppnlink |
129505269 |
| mediatype_str_mv |
n |
| isOA_txt |
false |
| hochschulschrift_bool |
false |
| author2_role |
oth oth oth oth oth oth oth oth oth oth |
| doi_str |
10.1073/pnas.1424220112 |
| up_date |
2024-07-03T14:35:28.917Z |
| _version_ |
1803568890691715072 |
| fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a2200265 4500</leader><controlfield tag="001">OLC1970275138</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230714175929.0</controlfield><controlfield tag="007">tu</controlfield><controlfield tag="008">160211s2015 xx ||||| 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1073/pnas.1424220112</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">PQ20160211</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)OLC1970275138</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)GBVOLC1970275138</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(PRQ)c2509-5b8e31a12ac4021aab6cb8127bc8c83f04480c79cbc49340e656ec3149178b83</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(KEY)0583363920150000112002708326bromodomainproteinbrd4controlshotairalongnoncoding</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">500</subfield><subfield code="q">DNB</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">570</subfield><subfield code="q">AVZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">LING</subfield><subfield code="2">fid</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">BIODIV</subfield><subfield code="2">fid</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Ricardo Komotar</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="4"><subfield code="a">The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2015</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">ohne Hilfsmittel zu benutzen</subfield><subfield code="b">n</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Band</subfield><subfield code="b">nc</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.</subfield></datafield><datafield tag="540" ind1=" " ind2=" "><subfield code="a">Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cell Proliferation - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Heterocyclic Compounds with 4 or More Rings - pharmacology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Nuclear Proteins - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Promoter Regions, Genetic - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RNA, Long Noncoding - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Nuclear Proteins - antagonists & inhibitors</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brain Neoplasms - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Nuclear Proteins - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Apoptosis - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcription Factors - antagonists & inhibitors</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glioblastoma - pathology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cell Proliferation - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brain Neoplasms - pathology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcription Factors - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Gene Expression Regulation, Neoplastic - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Xenograft Model Antitumor Assays - methods</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glioblastoma - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glioblastoma - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcription Factors - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RNA, Long Noncoding - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brain Neoplasms - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Observations</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Binding proteins</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glioblastoma multiforme</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Health aspects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genetic aspects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Epigenetic inheritance</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Gene expression</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Proteins</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Ribonucleic acid--RNA</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Epigenetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brain cancer</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cell growth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Amade Bregy</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Philipp Kapranov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Clara Penas</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Veronica Peschansky</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Georges St. Laurent</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Claes Wahlestedt</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Chiara Pastori</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Nagi G. Ayad</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jann N. Sarkaria</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Claude-Henry Volmar</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Proceedings of the National Academy of Sciences of the United States of America</subfield><subfield code="d">Washington, DC : NAS, 1877</subfield><subfield code="g">112(2015), 27, Seite 8326-8331</subfield><subfield code="w">(DE-627)129505269</subfield><subfield code="w">(DE-600)209104-5</subfield><subfield code="w">(DE-576)014909189</subfield><subfield code="x">0027-8424</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:112</subfield><subfield code="g">year:2015</subfield><subfield code="g">number:27</subfield><subfield code="g">pages:8326-8331</subfield></datafield><datafield tag="856" ind1="4" ind2="1"><subfield code="u">http://dx.doi.org/10.1073/pnas.1424220112</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://www.pnas.org/content/112/27/8326.abstract</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://www.ncbi.nlm.nih.gov/pubmed/26111795</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://search.proquest.com/docview/1696036543</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_OLC</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-LING</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-BIODIV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHY</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-CHE</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-MAT</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-DE-84</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-MAT</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_59</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">112</subfield><subfield code="j">2015</subfield><subfield code="e">27</subfield><subfield code="h">8326-8331</subfield></datafield></record></collection>
|
| score |
7.400259 |