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Article: Bcl-2 family members regulate anoxia-induced cell death.

Shroff, Emelyn H / Snyder, Colleen / Chandel, Navdeep S

2007 Volume 9, Issue 9, Page(s) 1405–1409

Abstract: The mechanisms underlying anoxia (0-0.5% oxygen)-induced cell death are not fully understood. Here we discuss the mechanisms by which cells undergo apoptosis in the absence of oxygen. Cell death during anoxia occurs via the intrinsic pathway of apoptosis. ...

Abstract	The mechanisms underlying anoxia (0-0.5% oxygen)-induced cell death are not fully understood. Here we discuss the mechanisms by which cells undergo apoptosis in the absence of oxygen. Cell death during anoxia occurs via the intrinsic pathway of apoptosis. Key regulators of apoptosis during anoxia are the Bcl-2 family of proteins. The pathway is initiated by the loss of function of the prosurvival Bcl-2 family members Mcl-1 and Bcl-2/Bcl-XL, resulting in Bax- or Bak-dependent release of cytochrome c and subsequent caspase-9-dependent cell death.
MeSH term(s)	Apoptosis ; Cell Death ; Homeostasis ; Hypoxia/pathology ; Hypoxia/physiopathology ; Models, Biological ; Proto-Oncogene Proteins c-bcl-2/physiology
Chemical Substances	Proto-Oncogene Proteins c-bcl-2
Language	English
Publishing date	2007-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2007.1731
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Article ; Online: Role of Bcl-2 family members in anoxia induced cell death.

Shroff, Emelyn H / Snyder, Colleen / Chandel, Navdeep S

Cell cycle (Georgetown, Tex.)

2007 Volume 6, Issue 7, Page(s) 807–809

Abstract: Anoxia, the condition of oxygen deprivation, induces apoptosis via the intrinsic apoptotic pathway. Cells deficient in both Bax and Bak do not undergo cell death during anoxia. However, the underlying mechanism of anoxia induced cell death is not well ... ...

Abstract	Anoxia, the condition of oxygen deprivation, induces apoptosis via the intrinsic apoptotic pathway. Cells deficient in both Bax and Bak do not undergo cell death during anoxia. However, the underlying mechanism of anoxia induced cell death is not well defined. Here we report our latest findings of two critical events that are required to induce cell death during anoxia. First, a key member of the Bcl-2 family of pro-survival proteins, Mcl-1, undergoes proteasomal-dependent degradation. The loss of Mcl-1 protein is independent of Bax or Bak indicating this is an early event in the apoptotic cascade. Second, cells inhibit the mitochondrial electron transport chain to negate the pro-survival function of Bcl-2/Bcl-X(L). These observations indicate that loss of pro-survival function is necessary for anoxia induced cell death.
MeSH term(s)	Animals ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/metabolism ; Cell Hypoxia/physiology ; Cell Survival/physiology ; Electron Transport/physiology ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Signal Transduction/physiology
Chemical Substances	Apoptosis Regulatory Proteins ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2007-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.6.7.4044
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Article ; Online: Nitric oxide induces cell death by regulating anti-apoptotic BCL-2 family members.

Snyder, Colleen M / Shroff, Emelyn H / Liu, Jing / Chandel, Navdeep S

PloS one

2009 Volume 4, Issue 9, Page(s) e7059

Abstract: Nitric oxide (NO) activates the intrinsic apoptotic pathway to induce cell death. However, the mechanism by which this pathway is activated in cells exposed to NO is not known. Here we report that BAX and BAK are activated by NO and that cytochrome c is ... ...

Abstract	Nitric oxide (NO) activates the intrinsic apoptotic pathway to induce cell death. However, the mechanism by which this pathway is activated in cells exposed to NO is not known. Here we report that BAX and BAK are activated by NO and that cytochrome c is released from the mitochondria. Cells deficient in Bax and Bak or Caspase-9 are completely protected from NO-induced cell death. The individual loss of the BH3-only proteins, Bim, Bid, Puma, Bad or Noxa, or Bid knockdown in Bim(-/-)/Puma(-/-) MEFs, does not prevent NO-induced cell death. Our data show that the anti-apoptotic protein MCL-1 undergoes ASK1-JNK1 mediated degradation upon exposure to NO, and that cells deficient in either Ask1 or Jnk1 are protected against NO-induced cell death. NO can inhibit the mitochondrial electron transport chain resulting in an increase in superoxide generation and peroxynitrite formation. However, scavengers of ROS or peroxynitrite do not prevent NO-induced cell death. Collectively, these data indicate that NO degrades MCL-1 through the ASK1-JNK1 axis to induce BAX/BAK-dependent cell death.
MeSH term(s)	Animals ; Apoptosis ; Caspase 9/metabolism ; Cytochromes c/metabolism ; Electron Transport Chain Complex Proteins/metabolism ; Fibroblasts/metabolism ; Gene Expression Regulation ; MAP Kinase Kinase Kinase 5/metabolism ; Mice ; Mitogen-Activated Protein Kinase 8/metabolism ; Multigene Family ; Myeloid Cell Leukemia Sequence 1 Protein ; Nitric Oxide/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Bak1 protein, mouse ; Bax protein, mouse ; Electron Transport Chain Complex Proteins ; Mcl1 protein, mouse ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein ; Nitric Oxide (31C4KY9ESH) ; Cytochromes c (9007-43-6) ; Mitogen-Activated Protein Kinase 8 (EC 2.7.11.24) ; MAP Kinase Kinase Kinase 5 (EC 2.7.11.25) ; Map3k5 protein, mouse (EC 2.7.11.25) ; Caspase 9 (EC 3.4.22.-)
Language	English
Publishing date	2009-09-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0007059
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Article ; Online: Characterization of MYC-induced tumorigenesis by in situ lipid profiling.

Perry, Richard H / Bellovin, David I / Shroff, Emelyn H / Ismail, Ali I / Zabuawala, Tahera / Felsher, Dean W / Zare, Richard N

Analytical chemistry

2013 Volume 85, Issue 9, Page(s) 4259–4262

Abstract: We apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to provide an in situ lipidomic profile of genetically modified tissues from a conditional transgenic mouse model of MYC-induced hepatocellular carcinoma (HCC). This unique, ...

Abstract	We apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to provide an in situ lipidomic profile of genetically modified tissues from a conditional transgenic mouse model of MYC-induced hepatocellular carcinoma (HCC). This unique, label-free approach of combining DESI-MSI with the ability to turn specific genes on and off has led to the discovery of highly specific lipid molecules associated with MYC-induced tumor onset. We are able to distinguish normal from MYC-induced malignant cells. Our approach provides a strategy to define a precise molecular picture at a resolution of about 200 μm that may be useful in identifying lipid molecules that define how the MYC oncogene initiates and maintains tumorigenesis.
MeSH term(s)	Animals ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Disease Models, Animal ; Lipid Metabolism/genetics ; Lipids/genetics ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Mice ; Mice, Transgenic ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Spectrometry, Mass, Electrospray Ionization
Chemical Substances	Lipids ; Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2013-04-18
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/ac400479j
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Article ; Online: Who Needs Big Health Sector Reforms Anyway? Seychelles' Road to UHC Provides Lessons for Sub-Saharan Africa and Island Nations.

Workie, Netsanet Walelign / Shroff, Emelyn / S Yazbeck, Abdo / Nguyen, Son Nam / Karamagi, Humphrey

Health systems and reform

2018 Volume 4, Issue 4, Page(s) 362–371

Abstract: The road to universal health coverage (UHC) needs not be driven by big reforms that include the initiation of health insurance, provider-funder separation, results-based financing, or other large health sector reforms advocated in many countries in sub- ... ...

Abstract	The road to universal health coverage (UHC) needs not be driven by big reforms that include the initiation of health insurance, provider-funder separation, results-based financing, or other large health sector reforms advocated in many countries in sub-Saharan Africa and elsewhere. The Seychelles experience, documented through a series of analytical products like public expenditure reviews and supporting surveys with assistance from the World Bank and World Health Organization (WHO), shows an alternative, more incremental reform road to UHC, with important lessons to the region and other small-population or island nations. Done well, in some countries, a basic supply-side funded, publicly owned and operated, and integrated health system can produce excellent health outcomes in a cost-effective and sustainable way. The article traces some of the factors that facilitated this success in the Seychelles, including high political commitment, strong voice and a downward accountability culture, strong public health functions, and an impressive investment in primary health care. These factors help explain past successes and also provide a good basis for adaptation of health systems to dramatic shifts in the epidemiological and demographic transitions, disease outbreaks, and rising public expectation and demand for high quality of care. Once again, how the Seychelles responds can show the way for other countries in the region and elsewhere regardless of the types of reforms countries engage in.
Language	English
Publishing date	2018-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2820935-7
ISSN	2328-8620 ; 2328-8620
ISSN (online)	2328-8620
ISSN	2328-8620
DOI	10.1080/23288604.2018.1513265
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Article ; Online: Nitric oxide induces cell death by regulating anti-apoptotic BCL-2 family members.

Colleen M Snyder / Emelyn H Shroff / Jing Liu / Navdeep S Chandel

PLoS ONE, Vol 4, Iss 9, p e

2009 Volume 7059

Abstract	Nitric oxide (NO) activates the intrinsic apoptotic pathway to induce cell death. However, the mechanism by which this pathway is activated in cells exposed to NO is not known. Here we report that BAX and BAK are activated by NO and that cytochrome c is released from the mitochondria. Cells deficient in Bax and Bak or Caspase-9 are completely protected from NO-induced cell death. The individual loss of the BH3-only proteins, Bim, Bid, Puma, Bad or Noxa, or Bid knockdown in Bim(-/-)/Puma(-/-) MEFs, does not prevent NO-induced cell death. Our data show that the anti-apoptotic protein MCL-1 undergoes ASK1-JNK1 mediated degradation upon exposure to NO, and that cells deficient in either Ask1 or Jnk1 are protected against NO-induced cell death. NO can inhibit the mitochondrial electron transport chain resulting in an increase in superoxide generation and peroxynitrite formation. However, scavengers of ROS or peroxynitrite do not prevent NO-induced cell death. Collectively, these data indicate that NO degrades MCL-1 through the ASK1-JNK1 axis to induce BAX/BAK-dependent cell death.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2009-09-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Characterization of MYC-Induced Tumorigenesis by in Situ Lipid Profiling

Perry, Richard H / Bellovin David I / Felsher Dean W / Ismail Ali I / Shroff Emelyn H / Zabuawala Tahera / Zare Richard N

Analytical chemistry. 2013 May 07, v. 85, no. 9

2013

Abstract	We apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to provide an in situ lipidomic profile of genetically modified tissues from a conditional transgenic mouse model of MYC-induced hepatocellular carcinoma (HCC). This unique, label-free approach of combining DESI-MSI with the ability to turn specific genes on and off has led to the discovery of highly specific lipid molecules associated with MYC-induced tumor onset. We are able to distinguish normal from MYC-induced malignant cells. Our approach provides a strategy to define a precise molecular picture at a resolution of about 200 Î¼m that may be useful in identifying lipid molecules that define how the MYC oncogene initiates and maintains tumorigenesis.
Keywords	animal models ; carcinogenesis ; desorption ; electrospray ionization mass spectrometry ; hepatoma ; image analysis ; lipid composition ; lipids ; oncogenes ; tissues ; transgenic animals
Language	English
Dates of publication	2013-0507
Size	p. 4259-4262.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/ac400479j
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism.

Shroff, Emelyn H / Eberlin, Livia S / Dang, Vanessa M / Gouw, Arvin M / Gabay, Meital / Adam, Stacey J / Bellovin, David I / Tran, Phuoc T / Philbrick, William M / Garcia-Ocana, Adolfo / Casey, Stephanie C / Li, Yulin / Dang, Chi V / Zare, Richard N / Felsher, Dean W

Proceedings of the National Academy of Sciences of the United States of America

2015 Volume 112, Issue 21, Page(s) 6539–6544

Abstract: The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show ... ...

Abstract	The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.
MeSH term(s)	Animals ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Cell Line, Tumor ; Disease Models, Animal ; Disease Progression ; Enzyme Inhibitors/pharmacology ; Genes, myc ; Genes, ras ; Glutaminase/antagonists & inhibitors ; Glutaminase/metabolism ; Glutamine/metabolism ; Humans ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Lipid Metabolism ; Mice ; Mice, SCID ; Mice, Transgenic ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Spectrometry, Mass, Electrospray Ionization ; Sulfides/pharmacology ; Thiadiazoles/pharmacology ; Up-Regulation
Chemical Substances	Enzyme Inhibitors ; RNA, Messenger ; RNA, Neoplasm ; Sulfides ; Thiadiazoles ; bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide ; Glutamine (0RH81L854J) ; Glutaminase (EC 3.5.1.2)
Language	English
Publishing date	2015-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1507228112
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Zs.A 1148: Show issues

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Article ; Online: BH3 peptides induce mitochondrial fission and cell death independent of BAX/BAK.

Shroff, Emelyn H / Snyder, Colleen M / Budinger, G R Scott / Jain, Manu / Chew, Teng-Leong / Khuon, Satya / Perlman, Harris / Chandel, Navdeep S

PloS one

2009 Volume 4, Issue 5, Page(s) e5646

Abstract: BH3 only proteins trigger cell death by interacting with pro- and anti-apoptotic members of the BCL-2 family of proteins. Here we report that BH3 peptides corresponding to the death domain of BH3-only proteins, which bind all the pro-survival BCL-2 ... ...

Abstract	BH3 only proteins trigger cell death by interacting with pro- and anti-apoptotic members of the BCL-2 family of proteins. Here we report that BH3 peptides corresponding to the death domain of BH3-only proteins, which bind all the pro-survival BCL-2 family proteins, induce cell death in the absence of BAX and BAK. The BH3 peptides did not cause the release of cytochrome c from isolated mitochondria or from mitochondria in cells. However, the BH3 peptides did cause a decrease in mitochondrial membrane potential but did not induce the opening of the mitochondrial permeability transition pore. Interestingly, the BH3 peptides induced mitochondria to undergo fission in the absence of BAX and BAK. The binding of BCL-X(L) with dynamin-related protein 1 (DRP1), a GTPase known to regulate mitochondrial fission, increased in the presence of BH3 peptides. These results suggest that pro-survival BCL-2 proteins regulate mitochondrial fission and cell death in the absence of BAX and BAK.
MeSH term(s)	Animals ; Caspase Inhibitors ; Cell Death/drug effects ; Cytochromes c/metabolism ; Embryo, Mammalian/cytology ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; Fibroblasts/ultrastructure ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Microinjections ; Microtubule-Associated Proteins/metabolism ; Mitochondria/drug effects ; Mitochondria/enzymology ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Peptides/pharmacology ; Protease Inhibitors/pharmacology ; Protein Binding/drug effects ; bcl-2-Associated X Protein/deficiency ; bcl-2-Associated X Protein/metabolism ; bcl-X Protein/deficiency ; bcl-X Protein/metabolism
Chemical Substances	Caspase Inhibitors ; Microtubule-Associated Proteins ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Peptides ; Protease Inhibitors ; bcl-2-Associated X Protein ; bcl-X Protein ; Cytochromes c (9007-43-6)
Language	English
Publishing date	2009-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0005646
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: High throughput automated chromatin immunoprecipitation as a platform for drug screening and antibody validation.

Wu, Angela R / Kawahara, Tiara L A / Rapicavoli, Nicole A / van Riggelen, Jan / Shroff, Emelyn H / Xu, Liwen / Felsher, Dean W / Chang, Howard Y / Quake, Stephen R

Lab on a chip

2012 Volume 12, Issue 12, Page(s) 2190–2198

Abstract: Chromatin immunoprecipitation (ChIP) is an assay for interrogating protein-DNA interactions that is increasingly being used for drug target discovery and screening applications. Currently the complexity of the protocol and the amount of hands-on time ... ...

Abstract	Chromatin immunoprecipitation (ChIP) is an assay for interrogating protein-DNA interactions that is increasingly being used for drug target discovery and screening applications. Currently the complexity of the protocol and the amount of hands-on time required for this assay limits its use to low throughput applications; furthermore, variability in antibody quality poses an additional obstacle in scaling up ChIP for large scale screening purposes. To address these challenges, we report HTChIP, an automated microfluidic-based platform for performing high-throughput ChIP screening measurements of 16 different targets simultaneously, with potential for further scale-up. From chromatin to analyzable PCR results only takes one day using HTChIP, as compared to several days up to one week for conventional protocols. HTChIP can also be used to test multiple antibodies and select the best performer for downstream ChIP applications, saving time and reagent costs of unsuccessful ChIP assays as a result of poor antibody quality. We performed a series of characterization assays to demonstrate that HTChIP can rapidly and accurately evaluate the epigenetic states of a cell, and that it is sensitive enough to detect the changes in the epigenetic state induced by a cytokine stimulant over a fine temporal resolution. With these results, we believe that HTChIP can introduce large improvements in routine ChIP, antibody screening, and drug screening efficiency, and further facilitate the use of ChIP as a valuable tool for research and discovery.
MeSH term(s)	Antibodies/immunology ; Automation ; Cell Proliferation/drug effects ; Chromatin Immunoprecipitation ; Drug Evaluation, Preclinical ; HeLa Cells ; High-Throughput Screening Assays ; Histones/metabolism ; Humans ; Microfluidic Analytical Techniques ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Necrosis Factor-alpha/pharmacology
Chemical Substances	Antibodies ; Histones ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2012-05-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2056646-3
ISSN	1473-0189 ; 1473-0197
ISSN (online)	1473-0189
ISSN	1473-0197
DOI	10.1039/c2lc21290k
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