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Article ; Online: Regulation of monocyte induced cell migration by the RNA binding protein, FXR1.

Le Tonqueze, O / Kollu, S / Lee, S / Al-Salah, M / Truesdell, S S / Vasudevan, S

2016 Volume 15, Issue 14, Page(s) 1874–1882

Abstract: FXR1 belongs to a family of RNA-binding proteins that play critical roles in post-transcriptional regulation of gene expression in immunity, development and cancer. FXR1 is associated with regulation of specific mRNAs in myocytes and macrophages. In ... ...

Abstract	FXR1 belongs to a family of RNA-binding proteins that play critical roles in post-transcriptional regulation of gene expression in immunity, development and cancer. FXR1 is associated with regulation of specific mRNAs in myocytes and macrophages. In quiescent cells (> 24 h of extended serum-starvation, ∼30-48 h or more), a spliced isoform of FXR1, FXR1a, promotes translation of the cytokine TNFα, independent of the effects of RNA levels. Here we examined the role of FXR1 in THP1 human monocytic leukemic cells that were grown in serum, as well as in early (24 h) serum-starvation conditions that demonstrates differences in gene expression mechanisms and is distinct from quiescent (> 24 h extended serum-starvation) cells. Global RNA profiling, conducted to investigate the role of FXR1 on mRNA levels, revealed that FXR1 affects levels of specific mRNAs in serum-grown and in early 24 h serum-starvation conditions. FXR1 decreases levels of several mRNAs, including as previously identified, CDKN1A (p21CIP1 or p21) mRNA in serum-grown cells. Interestingly, we find that FXR1 positively regulates mRNA levels of specific cytokines and chemokines in serum-grown and in early 24 h serum-starvation conditions. These include IL1β and CCL2 that control cell migration. Accordingly, depletion and overexpression of FXR1 decreased and increased levels of CCL2 mRNA. Consistent with the reduced levels of IL1β, CCL2 and other chemokines upon FXR1 depletion, our data reveal that depletion of FXR1 decreases the ability of these cells to induce cell migration of neighboring monocytic cells. These data reveal a new role of FXR1 in controlling induction of monocyte migration.
MeSH term(s)	Cell Line ; Cell Migration Assays ; Cell Movement/genetics ; Chemokines/genetics ; Chemokines/metabolism ; Culture Media, Serum-Free ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Interleukin-1beta/metabolism ; Monocytes/cytology ; Monocytes/metabolism ; Oligonucleotide Array Sequence Analysis ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Transcriptome/genetics
Chemical Substances	Chemokines ; Culture Media, Serum-Free ; FXR1 protein, human ; Interleukin-1beta ; RNA, Messenger ; RNA-Binding Proteins
Language	English
Publishing date	2016-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2016.1189040
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Article ; Online: Massively parallel analysis of human 3' UTRs reveals that AU-rich element length and registration predict mRNA destabilization.

Siegel, David A / Le Tonqueze, Olivier / Biton, Anne / Zaitlen, Noah / Erle, David J

G3 (Bethesda, Md.)

2021 Volume 12, Issue 1

Abstract: AU-rich elements (AREs) are 3' UTR cis-regulatory elements that regulate the stability of mRNAs. Consensus ARE motifs have been determined, but little is known about how differences in 3' UTR sequences that conform to these motifs affect their function. ... ...

Abstract	AU-rich elements (AREs) are 3' UTR cis-regulatory elements that regulate the stability of mRNAs. Consensus ARE motifs have been determined, but little is known about how differences in 3' UTR sequences that conform to these motifs affect their function. Here, we use functional annotation of sequences from 3' UTRs (fast-UTR), a massively parallel reporter assay (MPRA), to investigate the effects of 41,288 3' UTR sequence fragments from 4653 transcripts on gene expression and mRNA stability in Jurkat and Beas2B cells. Our analyses demonstrate that the length of an ARE and its registration (the first and last nucleotides of the repeating ARE motif) have significant effects on gene expression and stability. Based on this finding, we propose improved ARE classification and concomitant methods to categorize and predict the effect of AREs on gene expression and stability. Finally, to investigate the advantages of our general experimental design we examine other motifs including constitutive decay elements (CDEs), where we show that the length of the CDE stem-loop has a significant impact on steady-state expression and mRNA stability. We conclude that fast-UTR, in conjunction with our analytical approach, can produce improved yet simple sequence-based rules for predicting the activity of human 3' UTRs.
MeSH term(s)	3' Untranslated Regions ; Gene Expression Regulation ; Humans ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Regulatory Sequences, Nucleic Acid
Chemical Substances	3' Untranslated Regions ; RNA, Messenger
Language	English
Publishing date	2021-11-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1093/g3journal/jkab404
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Article: Identification of CELF1 RNA targets by CLIP-seq in human HeLa cells

Le Tonquèze, Olivier / Gschloessl, Bernhard / Legagneux, Vincent / Paillard, Luc / Audic, Yann

Genomics Data. 2016 June, v. 8

2016

Abstract: The specific interactions between RNA-binding proteins and their target RNAs are an essential level to control gene expression. By combining ultra-violet cross-linking and immunoprecipitation (CLIP) and massive SoliD sequencing we identified the RNAs ... ...

Abstract	The specific interactions between RNA-binding proteins and their target RNAs are an essential level to control gene expression. By combining ultra-violet cross-linking and immunoprecipitation (CLIP) and massive SoliD sequencing we identified the RNAs bound by the RNA-binding protein CELF1, in human HeLa cells. The CELF1 binding sites deduced from the sequence data allow characterizing specific features of CELF1-RNA association. We present therefore the first map of CELF1 binding sites in human cells.
Keywords	RNA ; RNA-binding proteins ; binding sites ; crosslinking ; gene expression ; humans ; precipitin tests
Language	English
Dates of publication	2016-06
Size	p. 97-103.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	2751131-5
ISSN	2213-5960
ISSN	2213-5960
DOI	10.1016/j.gdata.2016.04.009
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Article: Identification of CELF1 RNA targets by CLIP-seq in human HeLa cells.

Le Tonquèze, Olivier / Gschloessl, Bernhard / Legagneux, Vincent / Paillard, Luc / Audic, Yann

Genomics data

2016 Volume 8, Page(s) 97–103

Abstract	The specific interactions between RNA-binding proteins and their target RNAs are an essential level to control gene expression. By combining ultra-violet cross-linking and immunoprecipitation (CLIP) and massive SoliD sequencing we identified the RNAs bound by the RNA-binding protein CELF1, in human HeLa cells. The CELF1 binding sites deduced from the sequence data allow characterizing specific features of CELF1-RNA association. We present therefore the first map of CELF1 binding sites in human cells.
Language	English
Publishing date	2016-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2751131-5
ISSN	2213-5960
ISSN	2213-5960
DOI	10.1016/j.gdata.2016.04.009
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Article ; Online: Ribosome changes reprogram translation for chemosurvival in G0 leukemic cells.

Datta, Chandreyee / Truesdell, Samuel S / Wu, Keith Q / Bukhari, Syed I A / Ngue, Harrison / Buchanan, Brienna / Le Tonqueze, Olivier / Lee, Sooncheol / Kollu, Swapna / Granovetter, Madeleine A / Boukhali, Myriam / Kreuzer, Johannes / Batool, Maheen S / Balaj, Leonora / Haas, Wilhelm / Vasudevan, Shobha

Science advances

2022 Volume 8, Issue 43, Page(s) eabo1304

Abstract: Quiescent leukemic cells survive chemotherapy, with translation changes. Our data reveal that FXR1, a protein amplified in several aggressive cancers, is elevated in quiescent and chemo-treated leukemic cells and promotes chemosurvival. This suggests ... ...

Abstract	Quiescent leukemic cells survive chemotherapy, with translation changes. Our data reveal that FXR1, a protein amplified in several aggressive cancers, is elevated in quiescent and chemo-treated leukemic cells and promotes chemosurvival. This suggests undiscovered roles for this RNA- and ribosome-associated protein in chemosurvival. We find that FXR1 depletion reduces translation, with altered rRNAs, snoRNAs, and ribosomal proteins (RPs). FXR1 regulates factors that promote transcription and processing of ribosomal genes and snoRNAs. Ribosome changes in FXR1-overexpressing cells, including RPLP0/uL10 levels, activate eIF2α kinases. Accordingly, phospho-eIF2α increases, enabling selective translation of survival and immune regulators in FXR1-overexpressing cells. Overriding these genes or phospho-eIF2α with inhibitors reduces chemosurvival. Thus, elevated FXR1 in quiescent or chemo-treated leukemic cells alters ribosomes that trigger stress signals to redirect translation for chemosurvival.
Language	English
Publishing date	2022-10-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abo1304
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Article ; Online: A massively parallel 3' UTR reporter assay reveals relationships between nucleotide content, sequence conservation, and mRNA destabilization.

Litterman, Adam J / Kageyama, Robin / Le Tonqueze, Olivier / Zhao, Wenxue / Gagnon, John D / Goodarzi, Hani / Erle, David J / Ansel, K Mark

Genome research

2019 Volume 29, Issue 6, Page(s) 896–906

Abstract: Compared to coding sequences, untranslated regions of the transcriptome are not well conserved, and functional annotation of these sequences is challenging. Global relationships between nucleotide composition of 3' UTR sequences and their sequence ... ...

Abstract	Compared to coding sequences, untranslated regions of the transcriptome are not well conserved, and functional annotation of these sequences is challenging. Global relationships between nucleotide composition of 3' UTR sequences and their sequence conservation have been appreciated since mammalian genomes were first sequenced, but the functional relevance of these patterns remain unknown. We systematically measured the effect on gene expression of the sequences of more than 25,000 RNA-binding protein (RBP) binding sites in primary mouse T cells using a massively parallel reporter assay. GC-rich sequences were destabilizing of reporter mRNAs and come from more rapidly evolving regions of the genome. These sequences were more likely to be folded in vivo and contain a number of structural motifs that reduced accumulation of a heterologous reporter protein. Comparison of full-length 3' UTR sequences across vertebrate phylogeny revealed that strictly conserved 3' UTRs were GC-poor and enriched in genes associated with organismal development. In contrast, rapidly evolving 3' UTRs tended to be GC-rich and derived from genes involved in metabolism and immune responses. Cell-essential genes had lower GC content in their 3' UTRs, suggesting a connection between unstructured mRNA noncoding sequences and optimal protein production. By reducing gene expression, GC-rich RBP-occupied sequences act as a rapidly evolving substrate for gene regulatory interactions.
MeSH term(s)	3' Untranslated Regions ; Animals ; Base Composition ; Base Sequence ; Conserved Sequence ; Evolution, Molecular ; GC Rich Sequence ; Gene Expression ; Gene Expression Regulation ; Genes, Reporter ; Humans ; Mice ; Nucleic Acid Conformation ; RNA Stability ; RNA, Messenger/chemistry ; RNA, Messenger/genetics
Chemical Substances	3' Untranslated Regions ; RNA, Messenger
Language	English
Publishing date	2019-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.242552.118
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Zs.A 3729: 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 8: Show issues

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Article: MicroRNA-mediated posttranscriptional mechanisms of gene expression in proliferating and quiescent cancer cells

LeTonqueze, Olivier / Lee, Ju / Vasudevan, Shobha

RNA biology. 2012 June 1, v. 9, no. 6

2012

Abstract: MicroRNAs are small non-coding RNA regulators of gene expression that play important roles in critical biological processes, including cell division, self-renewal and cell state maintenance. Their deregulation leads to extensive clinical consequences in ... ...

Abstract	MicroRNAs are small non-coding RNA regulators of gene expression that play important roles in critical biological processes, including cell division, self-renewal and cell state maintenance. Their deregulation leads to extensive clinical consequences in tumorigenesis. Cancers demonstrate heterogeneity in their cell states implicated in their resistance and resurgence. Apart from proliferating cells, cancers harbor a small proportion of assorted quiescent cells that resist conventional therapeutics and contribute to cancer recurrence. MicroRNA expression, targets, microRNPs (microRNA-protein complexes) and their functions have been demonstrated to be regulated in distinct tumor cell states and as an adaptive response to stress signals in tumor-unfavorable environments. In turn, altered microRNPs and their modified post-transcriptional mechanisms of gene expression may contribute to tumor resistance and influence tumor progression. An understanding of distinct microRNA mechanisms in cancer cells would provide extensive insights into the versatile roles of microRNAs in the perpetuation of tumors and indicate potential therapeutic avenues.
Keywords	cancer recurrence ; carcinogenesis ; cell division ; cell proliferation ; gene expression ; microRNA ; neoplasm cells ; neoplasm progression ; neoplasms ; non-coding RNA ; stress response ; therapeutics
Language	English
Dates of publication	2012-0601
Size	p. 871-880.
Publishing place	Taylor & Francis
Document type	Article
ISSN	1555-8584
DOI	10.4161/rna.20806
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Article ; Online: Epithelial miR-141 regulates IL-13-induced airway mucus production.

Siddiqui, Sana / Johansson, Kristina / Joo, Alex / Bonser, Luke R / Koh, Kyung Duk / Le Tonqueze, Olivier / Bolourchi, Samaneh / Bautista, Rodriel A / Zlock, Lorna / Roth, Theodore L / Marson, Alexander / Bhakta, Nirav R / Ansel, K Mark / Finkbeiner, Walter E / Erle, David J / Woodruff, Prescott G

JCI insight

2021 Volume 6, Issue 5

Abstract: IL-13-induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role in mucus regulation is largely unexplored. We hypothesized that ... ...

Abstract	IL-13-induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role in mucus regulation is largely unexplored. We hypothesized that airway epithelial miRNAs play roles in IL-13-induced mucus regulation. miR-141 is highly expressed in human and mouse airway epithelium, is altered in bronchial brushings from asthmatic subjects at baseline, and is induced shortly after airway allergen exposure. We established a CRISPR/Cas9-based protocol to target miR-141 in primary human bronchial epithelial cells that were differentiated at air-liquid-interface, and goblet cell hyperplasia was induced by IL-13 stimulation. miR-141 disruption resulted in decreased goblet cell frequency, intracellular MUC5AC, and total secreted mucus. These effects correlated with a reduction in a goblet cell gene expression signature and enrichment of a basal cell gene expression signature defined by single cell RNA sequencing. Furthermore, intranasal administration of a sequence-specific mmu-miR-141-3p inhibitor in mice decreased Aspergillus-induced secreted mucus and mucus-producing cells in the lung and reduced airway hyperresponsiveness without affecting cellular inflammation. In conclusion, we have identified a miRNA that regulates pathological airway mucus production and is amenable to therapeutic manipulation through an inhaled route.
MeSH term(s)	Airway Remodeling ; Animals ; Aspergillus ; Asthma/metabolism ; Asthma/pathology ; CRISPR-Associated Protein 9 ; Cell Differentiation ; Cells, Cultured ; Clustered Regularly Interspaced Short Palindromic Repeats ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Female ; Goblet Cells/metabolism ; Goblet Cells/pathology ; Humans ; Interleukin-13/metabolism ; Lung/cytology ; Lung/metabolism ; Lung/pathology ; Male ; Metaplasia ; Mice, Inbred C57BL ; MicroRNAs/metabolism ; Mucin 5AC/metabolism ; Mucus/metabolism ; Mice
Chemical Substances	IL13 protein, human ; Interleukin-13 ; MIRN141 microRNA, human ; MUC5AC protein, human ; MicroRNAs ; Mucin 5AC ; CRISPR-Associated Protein 9 (EC 3.1.-)
Language	English
Publishing date	2021-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.139019
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Article ; Online: Chromosome wide analysis of CUGBP1 binding sites identifies the tetraspanin CD9 mRNA as a target for CUGBP1-mediated down-regulation.

Le Tonquèze, Olivier / Gschloessl, Bernhard / Namanda-Vanderbeken, Allen / Legagneux, Vincent / Paillard, Luc / Audic, Yann

Biochemical and biophysical research communications

2010 Volume 394, Issue 4, Page(s) 884–889

Abstract: CUGBP1 is an RNA-binding protein controlling alternative splicing, mRNA translation and stability. In this work we used a motif scoring approach to identify putative CUGBP1 binding sites for genes located on the human chromosome 12. This allowed us to ... ...

Abstract	CUGBP1 is an RNA-binding protein controlling alternative splicing, mRNA translation and stability. In this work we used a motif scoring approach to identify putative CUGBP1 binding sites for genes located on the human chromosome 12. This allowed us to identify the gene CD9 as a presumptive target for CUGBP1-mediated regulation. In a number of cancers, the tetraspanin CD9 is down-regulated, an event correlated with a bad prognostic. Using a combination of biochemical approaches and CUGBP1 knockdown, we showed that CUGBP1 directly controls CD9 expression.
MeSH term(s)	3' Untranslated Regions ; Antigens, CD/genetics ; Binding Sites ; CELF1 Protein ; Cells, Cultured ; Chromosomes, Human, Pair 12/genetics ; Computational Biology/methods ; Down-Regulation ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Membrane Glycoproteins/genetics ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Sequence Analysis, DNA/methods ; Tetraspanin-29
Chemical Substances	3' Untranslated Regions ; Antigens, CD ; CD9 protein, human ; CELF1 Protein ; CELF1 protein, human ; Membrane Glycoproteins ; RNA, Messenger ; RNA-Binding Proteins ; Tetraspanin-29
Language	English
Publishing date	2010-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2010.03.020
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Article ; Online: Identification of CUG-BP1/EDEN-BP target mRNAs in Xenopus tropicalis.

Graindorge, Antoine / Le Tonquèze, Olivier / Thuret, Raphaël / Pollet, Nicolas / Osborne, H Beverley / Audic, Yann

Nucleic acids research

2008 Volume 36, Issue 6, Page(s) 1861–1870

Abstract: The early development of many animals relies on the posttranscriptional regulations of maternally stored mRNAs. In particular, the translation of maternal mRNAs is tightly controlled during oocyte maturation and early mitotic cycles in Xenopus. The ... ...

Abstract	The early development of many animals relies on the posttranscriptional regulations of maternally stored mRNAs. In particular, the translation of maternal mRNAs is tightly controlled during oocyte maturation and early mitotic cycles in Xenopus. The Embryonic Deadenylation ElemeNt (EDEN) and its associated protein EDEN-BP are known to trigger deadenylation and translational silencing to several mRNAs bearing an EDEN. This Xenopus RNA-binding protein is an ortholog of the human protein CUG-BP1/CELF1. Five mRNAs, encoding cell cycle regulators and a protein involved in the notch pathway, have been identified as being deadenylated by EDEN/EDEN-BP. To identify new EDEN-BP targets, we immunoprecipitated EDEN-BP/mRNA complexes from Xenopus tropicalis egg extracts. We identified 153 mRNAs as new binding targets for EDEN-BP using microarrays. Sequence analyses of the 3' untranslated regions of the newly identified EDEN-BP targets reveal an enrichment in putative EDEN sequences. EDEN-BP binding to a subset of the targets was confirmed both in vitro and in vivo. Among the newly identified targets, Cdk1, a key player of oocyte maturation and cell cycle progression, is specifically targeted by its 3' UTR for an EDEN-BP-dependent deadenylation after fertilization.
MeSH term(s)	3' Untranslated Regions/chemistry ; 3' Untranslated Regions/metabolism ; Animals ; Binding Sites ; CDC2 Protein Kinase/metabolism ; Immunoprecipitation ; Oligonucleotide Array Sequence Analysis ; Ovum/metabolism ; RNA, Messenger/metabolism ; RNA-Binding Proteins/immunology ; RNA-Binding Proteins/metabolism ; Xenopus/genetics ; Xenopus/growth & development ; Xenopus Proteins/immunology ; Xenopus Proteins/metabolism
Chemical Substances	3' Untranslated Regions ; EDEN-specific RNA-binding protein, Xenopus ; RNA, Messenger ; RNA-Binding Proteins ; Xenopus Proteins ; CDC2 Protein Kinase (EC 2.7.11.22)
Language	English
Publishing date	2008-02-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkn031
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