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Article ; Online: Mitotic memories of gene activity.

Gonzalez, Inma / Molliex, Amandine / Navarro, Pablo

2021 Volume 69, Page(s) 41–47

Abstract: When cells enter mitosis, they undergo series of dramatic changes in their structure and function that severely hamper gene regulatory processes and gene transcription. This raises the question of how daughter cells efficiently recapitulate the gene ... ...

Abstract	When cells enter mitosis, they undergo series of dramatic changes in their structure and function that severely hamper gene regulatory processes and gene transcription. This raises the question of how daughter cells efficiently recapitulate the gene expression profile of their mother such that cell identity can be preserved. Here, we review recent evidence supporting the view that distinct chromatin-associated mechanisms of gene-regulatory inheritance assist daughter cells in the postmitotic reestablishment of gene activity with increased fidelity.
MeSH term(s)	Chromatin ; Chromosomes ; Gene Expression Regulation ; Humans ; Mitosis
Chemical Substances	Chromatin
Language	English
Publishing date	2021-01-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2020.12.009
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Article ; Online: A conserved NR5A1-responsive enhancer regulates SRY in testis-determination.

Houzelstein, Denis / Eozenou, Caroline / Lagos, Carlos F / Elzaiat, Maëva / Bignon-Topalovic, Joelle / Gonzalez, Inma / Laville, Vincent / Schlick, Laurène / Wankanit, Somboon / Madon, Prochi / Kirtane, Jyotsna / Athalye, Arundhati / Buonocore, Federica / Bigou, Stéphanie / Conway, Gerard S / Bohl, Delphine / Achermann, John C / Bashamboo, Anu / McElreavey, Ken

Nature communications

2024 Volume 15, Issue 1, Page(s) 2796

Abstract: The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY ... ...

Abstract	The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY expression to initiate testis-determination in humans. Comparative sequence analysis of SRY 5' regions in mammals identified an evolutionary conserved SF-1/NR5A1-binding motif within a 250 bp region of open chromatin located 5 kilobases upstream of the SRY transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of SRY. Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating SRY expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of SRY that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.
MeSH term(s)	Animals ; Female ; Humans ; Male ; Cell Line ; Gonadal Dysgenesis ; Mammals/genetics ; Regulatory Sequences, Nucleic Acid ; Sertoli Cells/metabolism ; Sex-Determining Region Y Protein/genetics ; Steroidogenic Factor 1/genetics ; Steroidogenic Factor 1/metabolism ; Testis/metabolism
Chemical Substances	NR5A1 protein, human ; Sex-Determining Region Y Protein ; Steroidogenic Factor 1 ; SRY protein, human ; HTRA2 protein, human (EC 3.4.21.108)
Language	English
Publishing date	2024-03-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47162-2
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Article ; Online: Mitotic bookmarking in development and stem cells.

Festuccia, Nicola / Gonzalez, Inma / Owens, Nick / Navarro, Pablo

Development (Cambridge, England)

2017 Volume 144, Issue 20, Page(s) 3633–3645

Abstract: The changes imposed on the nucleus, chromatin and its regulators during mitosis lead to the dismantlement of most gene regulatory processes. However, an increasing number of transcriptional regulators are being identified as capable of binding their ... ...

Abstract	The changes imposed on the nucleus, chromatin and its regulators during mitosis lead to the dismantlement of most gene regulatory processes. However, an increasing number of transcriptional regulators are being identified as capable of binding their genomic targets during mitosis. These so-called 'mitotic bookmarking factors' encompass transcription factors and chromatin modifiers that are believed to convey gene regulatory information from mother to daughter cells. In this Primer, we review mitotic bookmarking processes in development and stem cells and discuss the interest and potential importance of this concept with regard to epigenetic regulation and cell fate transitions involving cellular proliferation.
MeSH term(s)	Animals ; Cell Cycle ; Cell Differentiation ; Cell Lineage ; Cell Nucleus/metabolism ; Chromatin/metabolism ; Epigenesis, Genetic ; Gene Expression Regulation ; Gene Expression Regulation, Developmental ; Humans ; Mice ; Mitosis ; Stem Cells/cytology ; Transcription Factors/metabolism
Chemical Substances	Chromatin ; Transcription Factors
Language	English
Publishing date	2017--15
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.146522
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Article ; Online: The Epigenetic Paradox of Pluripotent ES Cells.

Festuccia, Nicola / Gonzalez, Inma / Navarro, Pablo

Journal of molecular biology

2016 Volume 429, Issue 10, Page(s) 1476–1503

Abstract: The propagation and maintenance of gene expression programs are at the foundation of the preservation of cell identity. A large and complex set of epigenetic mechanisms enables the long-term stability and inheritance of transcription states. A key ... ...

Abstract	The propagation and maintenance of gene expression programs are at the foundation of the preservation of cell identity. A large and complex set of epigenetic mechanisms enables the long-term stability and inheritance of transcription states. A key property of authentic epigenetic regulation is being independent from the instructive signals used for its establishment. This makes epigenetic regulation, particularly epigenetic silencing, extremely robust and powerful to lock regulatory states and stabilise cell identity. In line with this, the establishment of epigenetic silencing during development restricts cell potency and maintains the cell fate choices made by transcription factors (TFs). However, how more immature cells that have not yet established their definitive fate maintain their transitory identity without compromising their responsiveness to signalling cues remains unclear. A paradigmatic example is provided by pluripotent embryonic stem (ES) cells derived from a transient population of cells of the blastocyst. Here, we argue that ES cells represent an interesting "epigenetic paradox": even though they are captured in a self-renewing state characterised by extremely efficient maintenance of their identity, which is a typical manifestation of robust epigenetic regulation, they seem not to heavily rely on classical epigenetic mechanisms. Indeed, self-renewal strictly depends on the TFs that previously instructed their undifferentiated identity and relies on a particular signalling-dependent chromatin state where repressive chromatin marks play minor roles. Although this "epigenetic paradox" may underlie their exquisite responsiveness to developmental cues, it suggests that alternative mechanisms to faithfully propagate gene regulatory states might be prevalent in ES cells.
MeSH term(s)	Animals ; Cell Differentiation ; Chromatin/metabolism ; Embryonic Stem Cells/physiology ; Epigenesis, Genetic ; Gene Expression ; Humans ; Mice ; Pluripotent Stem Cells/physiology ; Signal Transduction ; Transcription Factors/metabolism
Chemical Substances	Chromatin ; Transcription Factors
Language	English
Publishing date	2016-12-15
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2016.12.009
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Article ; Online: The Epigenetic Paradox of Pluripotent ES Cells

Festuccia, Nicola / Gonzalez, Inma / Navarro Icaza, Pablo Asís

Journal of Molecular Biology. 2016,

2016

Abstract	The propagation and maintenance of gene expression programs are at the foundation of the preservation of cell identity. A large and complex set of epigenetic mechanisms enables the long-term stability and inheritance of transcription states. A key property of authentic epigenetic regulation is being independent from the instructive signals used for its establishment. This makes epigenetic regulation, particularly epigenetic silencing, extremely robust and powerful to lock regulatory states and stabilise cell identity. In line with this, the establishment of epigenetic silencing during development restricts cell potency and maintains the cell fate choices made by transcription factors (TFs). However, how more immature cells that have not yet established their definitive fate maintain their transitory identity without compromising their responsiveness to signalling cues remains unclear. A paradigmatic example is provided by pluripotent embryonic stem (ES) cells derived from a transient population of cells of the blastocyst. Here, we argue that ES cells represent an interesting “epigenetic paradox”: even though they are captured in a self-renewing state characterised by extremely efficient maintenance of their identity, which is a typical manifestation of robust epigenetic regulation, they seem not to heavily rely on classical epigenetic mechanisms. Indeed, self-renewal strictly depends on the TFs that previously instructed their undifferentiated identity and relies on a particular signalling-dependent chromatin state where repressive chromatin marks play minor roles. Although this “epigenetic paradox” may underlie their exquisite responsiveness to developmental cues, it suggests that alternative mechanisms to faithfully propagate gene regulatory states might be prevalent in ES cells.
Keywords	blastocyst ; chromatin ; embryonic stem cells ; epigenetics ; gene expression ; gene silencing ; genes ; signal transduction ; transcription (genetics) ; transcription factors ; TF ; ES ; PcG ; PRC ; ERV ; LTR ; LINE ; Brg1 ; MLL ; Ash2 ; Cfp1 ; Brm ; CHD ; NuRD ; Ep400 ; EB ; ERK ; Rb ; LIF ; ICM ; IAP ; BAF ; pluripotent embryonic stem cells ; ES cell self-renewal ; transcription factor
Language	English
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2016.12.009
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Article: Seasonal Variation of Health-Promoting Bioactives in Broccoli and Methyl-Jasmonate Pre-Harvest Treatments to Enhance Their Contents.

Nuñez-Gómez, Vanesa / Baenas, Nieves / Navarro-González, Inma / García-Alonso, Javier / Moreno, Diego A / González-Barrio, Rocío / Periago-Castón, Mª Jesús

Foods (Basel, Switzerland)

2020 Volume 9, Issue 10

Abstract: Broccoli is a source of bioactive compounds that provide an important nutritional value. The content of these compounds can vary depending on agronomic and environmental conditions, as well as on elicitation. In this study, three crop trials were carried ...

Abstract	Broccoli is a source of bioactive compounds that provide an important nutritional value. The content of these compounds can vary depending on agronomic and environmental conditions, as well as on elicitation. In this study, three crop trials were carried out to evaluate the effects of the cultivation season, the application of different dosages of methyl-jasmonate (MeJA) on the overall quality and on the total content of bioactive compounds of 'Parthenon' broccoli cultivated under the field conditions of southeastern Spain. Color parameters, chlorophyll content, total phenolic compounds, total flavonoids and antioxidant activity were measured to evaluate the overall quality. Moreover, individual carotenoids, phenolic compounds and glucosinolates were evaluated by high performance liquid chromatography with diode array detection (HPLC-DAD) and high performance liquid chromatography equipped with diode array detector coupled to mass spectrometer using electro spray ionization (HPLC-DAD-ESI/MS
Language	English
Publishing date	2020-09-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704223-6
ISSN	2304-8158
ISSN	2304-8158
DOI	10.3390/foods9101371
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Article: Seasonal Variation of Health-Promoting Bioactives in Broccoli and Methyl-Jasmonate Pre-Harvest Treatments to Enhance Their Contents

Nuñez-Gómez, Vanesa / Baenas, Nieves / Navarro-González, Inma / García-Alonso, Javier / Moreno, Diego A / González-Barrio, Rocío / Periago-Castón, Mª Jesús

Foods. 2020 Sept. 26, v. 9, no. 10

2020

Abstract	Broccoli is a source of bioactive compounds that provide an important nutritional value. The content of these compounds can vary depending on agronomic and environmental conditions, as well as on elicitation. In this study, three crop trials were carried out to evaluate the effects of the cultivation season, the application of different dosages of methyl-jasmonate (MeJA) on the overall quality and on the total content of bioactive compounds of ‘Parthenon’ broccoli cultivated under the field conditions of southeastern Spain. Color parameters, chlorophyll content, total phenolic compounds, total flavonoids and antioxidant activity were measured to evaluate the overall quality. Moreover, individual carotenoids, phenolic compounds and glucosinolates were evaluated by high performance liquid chromatography with diode array detection (HPLC-DAD) and high performance liquid chromatography equipped with diode array detector coupled to mass spectrometer using electro spray ionization (HPLC-DAD-ESI/MSⁿ). The content of total carotenoids, phenolic compounds and glucosinolates were higher in autumn compared with spring, showing increases of 2.8-fold, 2-fold and 1.2-fold, respectively. Moreover, a double application of MeJA increased the contents of total carotenoids, phenolic compounds and glucosinolates by 22%, 32% and 39%, respectively, relative to the untreated samples. Considering our results, the controlled and timely application of 250 µM MeJA to the aerial parts of the plants four days before harvest, on two consecutive days, seems to be a valid agronomic strategy to improve the health-promoting capacity of Parthenon broccoli, without compromising its overall quality.
Keywords	aerial parts ; antioxidant activity ; autumn ; bioactive compounds ; broccoli ; carotenoids ; chlorophyll ; color ; detection ; diodes ; environmental factors ; flavonoids ; foods ; glucosinolates ; health promotion ; high performance liquid chromatography ; ionization ; methyl jasmonate ; nutritive value ; phenolic compounds ; sampling ; seasonal variation ; spectrometers ; spring ; Spain
Language	English
Dates of publication	2020-0926
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
Note	NAL-light
ZDB-ID	2704223-6
ISSN	2304-8158
ISSN	2304-8158
DOI	10.3390/foods9101371
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Article ; Online: OCT4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 Lysine 9 methylation to pluripotency.

Bernard, Laure D / Dubois, Agnès / Heurtier, Victor / Fischer, Véronique / Gonzalez, Inma / Chervova, Almira / Tachtsidi, Alexandra / Gil, Noa / Owens, Nick / Bates, Lawrence E / Vandormael-Pournin, Sandrine / Silva, José C R / Ulitsky, Igor / Cohen-Tannoudji, Michel / Navarro, Pablo

Nucleic acids research

2022 Volume 50, Issue 13, Page(s) 7367–7379

Abstract: Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. Accordingly, in undifferentiated and pluripotent mouse ... ...

Abstract	Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. Accordingly, in undifferentiated and pluripotent mouse Embryonic Stem (ES) cells the global levels of H3K9 methylation are rather low and increase only upon differentiation. How global H3K9 methylation levels are coupled with the loss of pluripotency remains largely unknown. Here, we identify SUV39H1, a major H3K9 di- and tri-methylase, as an indirect target of the pluripotency network of Transcription Factors (TFs). We find that pluripotency TFs, principally OCT4, activate the expression of Suv39h1as, an antisense long non-coding RNA to Suv39h1. In turn, Suv39h1as downregulates Suv39h1 transcription in cis via a mechanism involving the modulation of the chromatin status of the locus. The targeted deletion of the Suv39h1as promoter region triggers increased SUV39H1 expression and H3K9me2 and H3K9me3 levels, affecting all heterochromatic regions, particularly peri-centromeric major satellites and retrotransposons. This increase in heterochromatinization efficiency leads to accelerated and more efficient commitment into differentiation. We report, therefore, a simple genetic circuitry coupling the genetic control of pluripotency with the global efficiency of H3K9 methylation associated with a major cell fate restriction, the irreversible loss of pluripotency.
MeSH term(s)	Animals ; Chromatin ; Histone Code ; Histones/genetics ; Histones/metabolism ; Methylation ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Mice ; Octamer Transcription Factor-3/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
Chemical Substances	Chromatin ; Histones ; Octamer Transcription Factor-3 ; Pou5f1 protein, mouse ; RNA, Long Noncoding ; Repressor Proteins ; Suv39h1 protein, mouse (EC 2.1.1.) ; Methyltransferases (EC 2.1.1.-)
Language	English
Publishing date	2022-08-10
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/gkac550
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Article ; Online: The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells.

Heurtier, Victor / Owens, Nick / Gonzalez, Inma / Mueller, Florian / Proux, Caroline / Mornico, Damien / Clerc, Philippe / Dubois, Agnes / Navarro, Pablo

Nature communications

2019 Volume 10, Issue 1, Page(s) 1109

Abstract: Transcription factor networks, together with histone modifications and signalling pathways, underlie the establishment and maintenance of gene regulatory architectures associated with the molecular identity of each cell type. However, how master ... ...

Abstract	Transcription factor networks, together with histone modifications and signalling pathways, underlie the establishment and maintenance of gene regulatory architectures associated with the molecular identity of each cell type. However, how master transcription factors individually impact the epigenomic landscape and orchestrate the behaviour of regulatory networks under different environmental constraints is only partially understood. Here, we show that the transcription factor Nanog deploys multiple distinct mechanisms to enhance embryonic stem cell self-renewal. In the presence of LIF, which fosters self-renewal, Nanog rewires the pluripotency network by promoting chromatin accessibility and binding of other pluripotency factors to thousands of enhancers. In the absence of LIF, Nanog blocks differentiation by sustaining H3K27me3, a repressive histone mark, at developmental regulators. Among those, we show that the repression of Otx2 plays a preponderant role. Our results underscore the versatility of master transcription factors, such as Nanog, to globally influence gene regulation during developmental processes.
MeSH term(s)	Animals ; Cell Line ; Cell Self Renewal/genetics ; Cell Self Renewal/physiology ; Enhancer Elements, Genetic ; Gene Expression Regulation ; Gene Regulatory Networks ; Histone Code/genetics ; Leukemia Inhibitory Factor/genetics ; Leukemia Inhibitory Factor/metabolism ; Mice ; Mouse Embryonic Stem Cells/cytology ; Mouse Embryonic Stem Cells/metabolism ; Nanog Homeobox Protein/genetics ; Nanog Homeobox Protein/metabolism ; Otx Transcription Factors/genetics ; Otx Transcription Factors/metabolism
Chemical Substances	Leukemia Inhibitory Factor ; Lif protein, mouse ; Nanog Homeobox Protein ; Nanog protein, mouse ; Otx Transcription Factors ; Otx2 protein, mouse
Language	English
Publishing date	2019-03-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-09041-z
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Article ; Online: High levels of dRYBP induce apoptosis in Drosophila imaginal cells through the activation of reaper and the requirement of trithorax, dredd and dFADD.

González, Inma / Busturia, Ana

Cell research

2009 Volume 19, Issue 6, Page(s) 747–757

Abstract: Drosophila RYBP (dRYBP; Ring1 and YY1 Binding Protein) is a Polycomb and trithorax interacting protein, whose homologous RYBP/DEDAF mammalian counterparts exhibit tumor cell-specific killing activity. Here we show that although endogenous dRYBP is not ... ...

Abstract	Drosophila RYBP (dRYBP; Ring1 and YY1 Binding Protein) is a Polycomb and trithorax interacting protein, whose homologous RYBP/DEDAF mammalian counterparts exhibit tumor cell-specific killing activity. Here we show that although endogenous dRYBP is not involved in developmental apoptosis, high levels of exogenous dRYBP induce apoptosis in all the imaginal discs of the fly, indicating that dRYBP apoptotic activity is not specific to tumor cells. We also show that dRYBP-induced apoptosis is inhibited by high levels of either p35 or DIAP1 (Drosophila Inhibitor of Apoptosis Protein 1), and requires the function of the pro-apoptotic REAPER, HID and GRIM proteins, the apical caspase DREDD, the adaptor dFADD protein as well as TRITHORAX (TRX), an epigenetic transcriptional regulator. Furthermore, we demonstrate that overexpression of TRX also induces apoptosis in the imaginal discs. Finally, we show that the expression of reaper-lacZ is upregulated both upon dRYBP-induced apoptosis and upon TRX-induced apoptosis in imaginal discs and that the reaper gene is a direct target of dRYBP in Drosophila embryos. Our results indicate that dRYBP triggers in a receptor-mediated apoptotic pathway that also includes TRX-dependent epigenetic regulation of gene expression.
MeSH term(s)	Animals ; Apoptosis ; Caspases/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Drosophila/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Fas-Associated Death Domain Protein/metabolism ; Inhibitor of Apoptosis Proteins/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Promoter Regions, Genetic ; Repressor Proteins/metabolism
Chemical Substances	Chromosomal Proteins, Non-Histone ; DIAP1 protein, Drosophila ; Drosophila Proteins ; FADD protein, Drosophila ; Fas-Associated Death Domain Protein ; Inhibitor of Apoptosis Proteins ; RYBP protein, Drosophila ; Repressor Proteins ; rpr protein, Drosophila ; trx protein, Drosophila ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Caspases (EC 3.4.22.-) ; dredd protein, Drosophila (EC 3.4.22.-)
Language	English
Publishing date	2009-02-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1319303-x
ISSN	1748-7838 ; 1001-0602
ISSN (online)	1748-7838
ISSN	1001-0602
DOI	10.1038/cr.2009.29
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