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Article: Exploring the Crosstalk Between

Zahr, Hind C / Jaalouk, Diana E

2018 Volume 9, Page(s) 231

Abstract: Mutations in ... ...

Abstract	Mutations in the
Language	English
Publishing date	2018-07-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2018.00231
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Article: Novel insights into the disease etiology of laminopathies.

Ho, Chin Yee / Jaalouk, Diana E / Lammerding, Jan

Rare diseases (Austin, Tex.)

2013 Volume 1, Issue 1, Page(s) e27002

Abstract: Laminopathies are a heterogeneous group of diseases that are caused by mutations in the nuclear envelope proteins lamins A and C. Laminopathies include dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and familial partial lipodystrophy. Despite ...

Abstract	Laminopathies are a heterogeneous group of diseases that are caused by mutations in the nuclear envelope proteins lamins A and C. Laminopathies include dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and familial partial lipodystrophy. Despite their near-ubiquitous expression, most laminopathies involve highly tissue-specific phenotypes, often affecting skeletal and cardiac muscle. The underlying mechanism(s) remain incompletely understood. We recently reported that altered actin dynamics in lamin A/C-deficient and mutant cells disturb nuclear shuttling of the transcriptional co-activator MKL1, which is critical for cardiac function. Expression of the inner nuclear membrane protein emerin rescues MKL1 translocation through modulating actin dynamics. Here, we elaborate on these findings, discuss new insights into the role of nuclear actin in MKL1activity, and demonstrate that primary human skin fibroblasts from a patient with dilated cardiomyopathy have impaired MKL1 nuclear translocation. These findings further strengthen the relevance of impaired MKL1 signaling as a potential contributor to the disease mechanism in laminopathies.
Language	English
Publishing date	2013-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2817861-0
ISSN	2167-5511
ISSN	2167-5511
DOI	10.4161/rdis.27002
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Article ; Online: Mechanotransduction gone awry.

Jaalouk, Diana E / Lammerding, Jan

Nature reviews. Molecular cell biology

2009 Volume 10, Issue 1, Page(s) 63–73

Abstract: Cells sense their physical surroundings through mechanotransduction - that is, by translating mechanical forces and deformations into biochemical signals such as changes in intracellular calcium concentration or by activating diverse signalling pathways. ...

Abstract	Cells sense their physical surroundings through mechanotransduction - that is, by translating mechanical forces and deformations into biochemical signals such as changes in intracellular calcium concentration or by activating diverse signalling pathways. In turn, these signals can adjust cellular and extracellular structure. This mechanosensitive feedback modulates cellular functions as diverse as migration, proliferation, differentiation and apoptosis, and is crucial for organ development and homeostasis. Consequently, defects in mechanotransduction - often caused by mutations or misregulation of proteins that disturb cellular or extracellular mechanics - are implicated in the development of various diseases, ranging from muscular dystrophies and cardiomyopathies to cancer progression and metastasis.
MeSH term(s)	Aging, Premature/physiopathology ; Animals ; Cardiomegaly/physiopathology ; Humans ; Mechanotransduction, Cellular/physiology ; Muscular Dystrophies/physiopathology ; Mutation ; Neoplasms/physiopathology
Language	English
Publishing date	2009-02-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/nrm2597
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Zs.A 5446: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 26: Show issues

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Article ; Online: Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics.

Ho, Chin Yee / Jaalouk, Diana E / Vartiainen, Maria K / Lammerding, Jan

Nature

2013 Volume 497, Issue 7450, Page(s) 507–511

Abstract: Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery-Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular ... ...

Abstract	Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery-Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison-Gilford progeria syndrome. Most LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and altered interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes. Here we report in mice that lamin-A/C-deficient (Lmna(-/-)) and Lmna(N195K/N195K) mutant cells have impaired nuclear translocation and downstream signalling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function. Altered nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna(-/-) and Lmna(N195K/N195K) mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmna mutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease aetiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.
MeSH term(s)	Actins/chemistry ; Actins/metabolism ; Active Transport, Cell Nucleus ; Animals ; Cell Nucleus/metabolism ; Cells, Cultured ; Cytoskeleton/metabolism ; Fibroblasts/metabolism ; Gene Expression Regulation ; Heart/growth & development ; Lamin Type A/deficiency ; Lamin Type A/genetics ; Lamin Type A/metabolism ; Male ; Membrane Proteins/metabolism ; Mice ; Mutation ; Myocardium/metabolism ; Nuclear Proteins/metabolism ; Serum Response Factor/metabolism ; Signal Transduction ; Trans-Activators/metabolism
Chemical Substances	Actins ; Lamin Type A ; Membrane Proteins ; Mrtfa protein, mouse ; Nuclear Proteins ; Serum Response Factor ; Trans-Activators ; emerin ; lamin C
Language	English
Publishing date	2013-05-05
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, P.H.S.
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature12105
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 9: Show issues
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Article ; Online: Identification of targeting peptides for ischemic myocardium by in vivo phage display.

Kanki, Sachiko / Jaalouk, Diana E / Lee, Samuel / Yu, Alvin Y C / Gannon, Joseph / Lee, Richard T

Journal of molecular and cellular cardiology

2011 Volume 50, Issue 5, Page(s) 841–848

Abstract: Therapies selectively targeting ischemic myocardium could be applied by intravenous injection. Here, we report an approach for ischemic tissue-selective targeting based on in vivo screening of random peptide sequences using phage display. We performed in ...

Abstract	Therapies selectively targeting ischemic myocardium could be applied by intravenous injection. Here, we report an approach for ischemic tissue-selective targeting based on in vivo screening of random peptide sequences using phage display. We performed in vivo biopanning using a phage library in a rat model of ischemia-reperfusion and identified three peptide motifs, CSTSMLKAC, CKPGTSSYC, and CPDRSVNNC, that exhibited preferential binding to ischemic heart tissue compared to normal heart as well as other control organs. The CSTSMLKAC sequence was capable of mediating selective homing of phage to ischemic heart tissue. The CSTSMLKAC peptide was then made as a fusion protein with Sumo-mCherry and injected intravenously in a mouse model of myocardial ischemia-reperfusion injury; subsequently, bio-distribution of Sumo-mCherry-CSTSMLKAC was measured with quantitative ELISA. The targeting peptide led to a significant increase in homing to ischemic left ventricle compared to tissues from non-ischemic left ventricle, the right ventricle, lung, liver, spleen, skeletal muscle, and brain (all p<0.001). These results indicate that the peptide sequence CSTSMLKAC represents a novel molecular tool that may be useful in targeting ischemic tissue and delivering bioengineered proteins into the injured myocardium by systemic intravenous administration.
MeSH term(s)	Amino Acid Sequence ; Animals ; Male ; Mice ; Myocardial Ischemia/drug therapy ; Peptide Library ; Peptides/chemistry ; Peptides/therapeutic use ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Peptide Library ; Peptides
Language	English
Publishing date	2011-02-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2011.02.003
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Zs.A 426: Show issues

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Article ; Online: The interaction between nesprins and sun proteins at the nuclear envelope is critical for force transmission between the nucleus and cytoskeleton.

Lombardi, Maria L / Jaalouk, Diana E / Shanahan, Catherine M / Burke, Brian / Roux, Kyle J / Lammerding, Jan

The Journal of biological chemistry

2011 Volume 286, Issue 30, Page(s) 26743–26753

Abstract: Maintaining physical connections between the nucleus and the cytoskeleton is important for many cellular processes that require coordinated movement and positioning of the nucleus. Nucleo-cytoskeletal coupling is also necessary to transmit extracellular ... ...

Abstract	Maintaining physical connections between the nucleus and the cytoskeleton is important for many cellular processes that require coordinated movement and positioning of the nucleus. Nucleo-cytoskeletal coupling is also necessary to transmit extracellular mechanical stimuli across the cytoskeleton to the nucleus, where they may initiate mechanotransduction events. The LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, formed by the interaction of nesprins and SUN proteins at the nuclear envelope, can bind to nuclear and cytoskeletal elements; however, its functional importance in transmitting intracellular forces has never been directly tested. This question is particularly relevant since recent findings have linked nesprin mutations to muscular dystrophy and dilated cardiomyopathy. Using biophysical assays to assess intracellular force transmission and associated cellular functions, we identified the LINC complex as a critical component for nucleo-cytoskeletal force transmission. Disruption of the LINC complex caused impaired propagation of intracellular forces and disturbed organization of the perinuclear actin and intermediate filament networks. Although mechanically induced activation of mechanosensitive genes was normal (suggesting that nuclear deformation is not required for mechanotransduction signaling) cells exhibited other severe functional defects after LINC complex disruption; nuclear positioning and cell polarization were impaired in migrating cells and in cells plated on micropatterned substrates, and cell migration speed and persistence time were significantly reduced. Taken together, our findings suggest that the LINC complex is critical for nucleo-cytoskeletal force transmission and that LINC complex disruption can result in defects in cellular structure and function that may contribute to the development of muscular dystrophies and cardiomyopathies.
MeSH term(s)	Animals ; Cardiomyopathies/genetics ; Cardiomyopathies/metabolism ; Cell Line, Transformed ; Cytoskeleton/genetics ; Cytoskeleton/metabolism ; Humans ; Mechanotransduction, Cellular/physiology ; Mice ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Muscular Dystrophies/genetics ; Muscular Dystrophies/metabolism ; Nuclear Envelope/genetics ; Nuclear Envelope/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism
Chemical Substances	Multiprotein Complexes ; Nuclear Proteins
Language	English
Publishing date	2011-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M111.233700
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Uc I Zs.108: Show issues

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Article ; Online: Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling.

Zwerger, Monika / Jaalouk, Diana E / Lombardi, Maria L / Isermann, Philipp / Mauermann, Monika / Dialynas, George / Herrmann, Harald / Wallrath, Lori L / Lammerding, Jan

Human molecular genetics

2013 Volume 22, Issue 12, Page(s) 2335–2349

Abstract: Lamins are intermediate filament proteins that assemble into a meshwork underneath the inner nuclear membrane, the nuclear lamina. Mutations in the LMNA gene, encoding lamins A and C, cause a variety of diseases collectively called laminopathies. The ... ...

Abstract	Lamins are intermediate filament proteins that assemble into a meshwork underneath the inner nuclear membrane, the nuclear lamina. Mutations in the LMNA gene, encoding lamins A and C, cause a variety of diseases collectively called laminopathies. The disease mechanism for these diverse conditions is not well understood. Since lamins A and C are fundamental determinants of nuclear structure and stability, we tested whether defects in nuclear mechanics could contribute to the disease development, especially in laminopathies affecting mechanically stressed tissue such as muscle. Using skin fibroblasts from laminopathy patients and lamin A/C-deficient mouse embryonic fibroblasts stably expressing a broad panel of laminopathic lamin A mutations, we found that several mutations associated with muscular dystrophy and dilated cardiomyopathy resulted in more deformable nuclei; in contrast, lamin mutants responsible for diseases without muscular phenotypes did not alter nuclear deformability. We confirmed our results in intact muscle tissue, demonstrating that nuclei of transgenic Drosophila melanogaster muscle expressing myopathic lamin mutations deformed more under applied strain than controls. In vivo and in vitro studies indicated that the loss of nuclear stiffness resulted from impaired assembly of mutant lamins into the nuclear lamina. Although only a subset of lamin mutations associated with muscular diseases caused increased nuclear deformability, almost all mutations tested had defects in force transmission between the nucleus and cytoskeleton. In conclusion, our results indicate that although defective nuclear stability may play a role in the development of muscle diseases, other factors, such as impaired nucleo-cytoskeletal coupling, likely contribute to the muscle phenotype.
MeSH term(s)	Animals ; Cells, Cultured ; Cytoskeleton/chemistry ; Cytoskeleton/genetics ; Cytoskeleton/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Fibroblasts/metabolism ; Humans ; Lamin Type A/chemistry ; Lamin Type A/genetics ; Lamin Type A/metabolism ; Mice ; Mice, Knockout ; Muscles/chemistry ; Muscles/metabolism ; Muscular Diseases/genetics ; Muscular Diseases/metabolism ; Mutation ; Nuclear Lamina/chemistry ; Nuclear Lamina/genetics ; Nuclear Lamina/metabolism ; Protein Stability
Chemical Substances	Lamin Type A ; lamin C
Language	English
Publishing date	2013-02-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddt079
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Article ; Online: Inhibition of histone deacetylation in 293GPG packaging cell line improves the production of self-inactivating MLV-derived retroviral vectors.

Jaalouk, Diana E / Crosato, Milena / Brodt, Pnina / Galipeau, Jacques

Virology journal

2006 Volume 3, Page(s) 27

Abstract: Background: Self-inactivating retroviral vectors (SIN) are often associated with very low titers. Promoter elements embedded within SIN designs may suppress transcription of packageable retroviral RNA which in turn results in titer reduction. We tested ... ...

Abstract	Background: Self-inactivating retroviral vectors (SIN) are often associated with very low titers. Promoter elements embedded within SIN designs may suppress transcription of packageable retroviral RNA which in turn results in titer reduction. We tested whether this dominant-negative effect involves histone acetylation state. We designed an MLV-derived SIN vector using the cytomegalovirus immediate early enhancer-promoter (CMVIE) as an embedded internal promoter (SINCMV) and transfected the pantropic 293GPG packaging cell line. Results: The SINCMV retroviral producer had uniformly very low titers (approximately 10,000 infectious retroparticles per ml). Northern blot showed low levels of expression of retroviral mRNA in producer cells in particular that of packageable RNA transcript. Treatment of the producers with the histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A reversed transcriptional suppression and resulted in an average 106.3 +/- 4.6 - fold (P = 0.002) and 15.5 +/- 1.3 - fold increase in titer (P = 0.008), respectively. A histone gel assay confirmed increased histone acetylation in treated producer cells. Conclusion: These results show that SIN retrovectors incorporating strong internal promoters such as CMVIE, are susceptible to transcriptional silencing and that treatment of the producer cells with HDAC inhibitors can overcome this blockade suggesting that histone deacetylation is implicated in the mechanism of transcriptional suppression.
MeSH term(s)	Acetylation/drug effects ; Butyrates/pharmacology ; Cell Line ; Gene Expression Regulation/drug effects ; Genetic Engineering ; Genetic Vectors/genetics ; Histones/metabolism ; Humans ; Hydroxamic Acids/pharmacology ; Leukemia Virus, Murine/drug effects ; Leukemia Virus, Murine/genetics ; Leukemia Virus, Murine/physiology ; RNA, Viral/metabolism ; Transcription, Genetic/drug effects ; Transfection/methods ; Virus Replication/drug effects
Chemical Substances	Butyrates ; Histones ; Hydroxamic Acids ; RNA, Viral ; trichostatin A (3X2S926L3Z)
Language	English
Publishing date	2006-04-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1743-422X
ISSN (online)	1743-422X
DOI	10.1186/1743-422X-3-27
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Article ; Online: A self-inactivating retrovector incorporating the IL-2 promoter for activation-induced transgene expression in genetically engineered T-cells.

Jaalouk, Diana E / Lejeune, Laurence / Couture, Clément / Galipeau, Jacques

Virology journal

2006 Volume 3, Page(s) 97

Abstract: Background: T-cell activation leads to signaling pathways that ultimately result in induction of gene transcription from the interleukin-2 (IL-2) promoter. We hypothesized that the IL-2 promoter or its synthetic derivatives can lead to T-cell specific, ... ...

Abstract	Background: T-cell activation leads to signaling pathways that ultimately result in induction of gene transcription from the interleukin-2 (IL-2) promoter. We hypothesized that the IL-2 promoter or its synthetic derivatives can lead to T-cell specific, activation-induced transgene expression. Our objective was to develop a retroviral vector for stable and activation-induced transgene expression in T-lymphocytes. Results: First, we compared the transcriptional potency of the full-length IL-2 promoter with that of a synthetic promoter composed of 3 repeats of the Nuclear Factor of Activated T-Cells (NFAT) element following activation of transfected Jurkat T-cells expressing the large SV40 T antigen (Jurkat TAg). Although the NFAT3 promoter resulted in a stronger induction of luciferase reporter expression post stimulation, the basal levels of the IL-2 promoter-driven reporter expression were much lower indicating that the IL-2 promoter can serve as a more stringent activation-dependent promoter in T-cells. Based on this data, we generated a self-inactivating retroviral vector with the full-length human IL-2 promoter, namely SINIL-2pr that incorporated the enhanced green fluorescent protein (EGFP) fused to herpes simplex virus thymidine kinase as a reporter/suicide "bifunctional" gene. Subsequently, Vesicular Stomatitis Virus-G Protein pseudotyped retroparticles were generated for SINIL-2pr and used to transduce the Jurkat T-cell line and the ZAP-70-deficient P116 cell line. Flow cytometry analysis showed that EGFP expression was markedly enhanced post co-stimulation of the gene-modified cells with 1 muM ionomycin and 10 ng/ml phorbol 12-myristate 13-acetate (PMA). This activation-induced expression was abrogated when the cells were pretreated with 300 nM cyclosporin A. Conclusion: These results demonstrate that the SINIL-2pr retrovector leads to activation-inducible transgene expression in Jurkat T-cell lines. We propose that this design can be potentially exploited in several cellular immunotherapy applications.
MeSH term(s)	Cyclosporine/pharmacology ; Dependovirus/genetics ; Genetic Engineering ; Humans ; Interleukin-2/genetics ; Jurkat Cells ; Luciferases/genetics ; Lymphocyte Activation ; NFATC Transcription Factors/genetics ; Promoter Regions, Genetic ; Retroviridae/genetics ; T-Lymphocytes/metabolism ; Transgenes
Chemical Substances	Interleukin-2 ; NFATC Transcription Factors ; NFATC4 protein, human ; Cyclosporine (83HN0GTJ6D) ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2006-11-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1743-422X
ISSN (online)	1743-422X
DOI	10.1186/1743-422X-3-97
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Inhibition of histone deacetylation in 293GPG packaging cell line improves the production of self-inactivating MLV-derived retroviral vectors

Jaalouk, Diana E / Crosato, Milena / Brodt, Pnina / Galipeau, Jacques

Virology journal. 2006 Dec., v. 3, no. 1

2006

Abstract: BACKGROUND: Self-inactivating retroviral vectors (SIN) are often associated with very low titers. Promoter elements embedded within SIN designs may suppress transcription of packageable retroviral RNA which in turn results in titer reduction. We tested ... ...

Abstract	BACKGROUND: Self-inactivating retroviral vectors (SIN) are often associated with very low titers. Promoter elements embedded within SIN designs may suppress transcription of packageable retroviral RNA which in turn results in titer reduction. We tested whether this dominant-negative effect involves histone acetylation state. We designed an MLV-derived SIN vector using the cytomegalovirus immediate early enhancer-promoter (CMVIE) as an embedded internal promoter (SINCMV) and transfected the pantropic 293GPG packaging cell line. RESULTS: The SINCMV retroviral producer had uniformly very low titers (~10,000 infectious retroparticles per ml). Northern blot showed low levels of expression of retroviral mRNA in producer cells in particular that of packageable RNA transcript. Treatment of the producers with the histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A reversed transcriptional suppression and resulted in an average 106.3 ± 4.6 – fold (P = 0.002) and 15.5 ± 1.3 – fold increase in titer (P = 0.008), respectively. A histone gel assay confirmed increased histone acetylation in treated producer cells. CONCLUSION: These results show that SIN retrovectors incorporating strong internal promoters such as CMVIE, are susceptible to transcriptional silencing and that treatment of the producer cells with HDAC inhibitors can overcome this blockade suggesting that histone deacetylation is implicated in the mechanism of transcriptional suppression.
Keywords	Northern blotting ; acetylation ; cell lines ; gels ; histone deacetylase ; histones ; messenger RNA ; sodium butyrate ; transcription (genetics) ; virology
Language	English
Dates of publication	2006-12
Size	p. 27.
Publishing place	BioMed Central
Document type	Article
ZDB-ID	2160640-7
ISSN	1743-422X
ISSN	1743-422X
DOI	10.1186/1743-422X-3-27
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