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Article: FOXO transcription factors as regulators of immune homeostasis: molecules to die for?

Birkenkamp, Kim U / Coffer, Paul J

Journal of immunology (Baltimore, Md. : 1950)

2003 Volume 171, Issue 4, Page(s) 1623–1629

Abstract: Regulation of phosphatidylinositol 3-kinase (PI3K) activity has been demonstrated to be critical for correct lymphocyte function. The molecular targets of this lipid kinase have been the subject of extensive research, and many functional effects of PI3K ... ...

Abstract	Regulation of phosphatidylinositol 3-kinase (PI3K) activity has been demonstrated to be critical for correct lymphocyte function. The molecular targets of this lipid kinase have been the subject of extensive research, and many functional effects of PI3K activation are thought to be mediated by the serine-threonine kinase protein kinase B (PKB/c-akt). Genetic analyses in the nematode worm Caenorhabditis elegans have identified a novel PI3K-regulated signaling pathway that regulates organism lifespan through inhibition of a Forkhead (FOX) transcription factor, DAF-16. Recent studies have subsequently revealed an evolutionarily conserved signaling module in higher eukaryotes in which PKB can directly phosphorylate and inactive a family of Forkhead box class O (FOXO) transcription factors. Phosphorylation results in nuclear exclusion and inhibition of transcription. FOXO transcription factors have been found to play critical roles in regulation of proliferation, apoptosis and control of oxidative stress. This occurs through both activation and repression of target gene expression by multiple mechanisms. Here the regulation and function of these transcription factors is discussed with specific relevance to immune homeostasis. A greater understanding of the regulation and function of this signaling pathway in lymphocytes may provide novel therapeutic opportunities for immune diseases.
MeSH term(s)	Animals ; Apoptosis/immunology ; Cell Survival/immunology ; DNA-Binding Proteins ; Drosophila Proteins/antagonists & inhibitors ; Drosophila Proteins/physiology ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Homeostasis/immunology ; Nerve Tissue Proteins ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/physiology ; Protein Isoforms/antagonists & inhibitors ; Protein Isoforms/physiology ; Signal Transduction/immunology ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/physiology
Chemical Substances	DNA-Binding Proteins ; Drosophila Proteins ; FOXO protein, Drosophila ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Foxd1 protein, mouse ; Foxo1 protein, mouse ; Nerve Tissue Proteins ; Nuclear Proteins ; Protein Isoforms ; Transcription Factors
Language	English
Publishing date	2003-07-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.171.4.1623
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Article ; Online: A prospective, observational, open-label, multicentre study to investigate the daily treatment practice of ranibizumab in patients with neovascular age-related macular degeneration.

van Asten, Freekje / Evers-Birkenkamp, Kim U / van Lith-Verhoeven, Janneke J C / de Jong-Hesse, Yvonne / Hoppenreijs, Vincent P T / Hommersom, Richard F / Scholten, Agnes M / Hoyng, Carel B / Klaver, Johannes H J

Acta ophthalmologica

2015 Volume 93, Issue 2, Page(s) 126–133

Abstract: Purpose: The HELIOS (Health Economics with Lucentis in Observational Settings) study was designed on request of the Dutch Health Authority for an observational study to assess the effectiveness and safety of ranibizumab for neovascular age-related ... ...

Abstract	Purpose: The HELIOS (Health Economics with Lucentis in Observational Settings) study was designed on request of the Dutch Health Authority for an observational study to assess the effectiveness and safety of ranibizumab for neovascular age-related macular degeneration (wet AMD) in daily practice. Methods: The HELIOS study was a 2-year prospective, observational, open-label, multicentre study involving 14 sites. Patients with wet AMD were enrolled and observed for a period of 24 months. The data were collected at baseline and at the visits closest around the time-points 3, 6, 12, 18 and 24 months after inclusion. Results: Treatment with ranibizumab resulted in prevention of vision loss. The mean ETDRS score increased from 45.1 letters at baseline to 48.5 letters at 24 months. This was achieved with a mean of 7.8 injections over 24 months. Stabilization of visual acuity was also reflected by the scores on the quality of life EQ-5D questionnaire, which did not significantly change over the study period. The more subjective EQ-VAS questionnaire showed an overall improvement. The VFQ-25 questionnaire was also mostly stable over time. After 24 months, 32.2% of the patients gained ≥1 letter and 17.1% gained >15 letters. Patients completing the loading phase were better responders, as demonstrated by increased long-term visual acuity. In addition, ranibizumab was well tolerated and had a safety profile commonly seen in routine clinical practice. Conclusion: This study demonstrates that also in daily practice ranibizumab was effective in preventing vision loss over a period of 24 months. No new safety findings were identified.
MeSH term(s)	Aged ; Aged, 80 and over ; Angiogenesis Inhibitors/administration & dosage ; Angiogenesis Inhibitors/adverse effects ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Female ; Humans ; Intravitreal Injections ; Male ; Prospective Studies ; Quality of Life/psychology ; Ranibizumab ; Sickness Impact Profile ; Surveys and Questionnaires ; Tomography, Optical Coherence ; Treatment Outcome ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Vision Disorders/prevention & control ; Visual Acuity/physiology ; Wet Macular Degeneration/drug therapy ; Wet Macular Degeneration/physiopathology ; Wet Macular Degeneration/psychology
Chemical Substances	Angiogenesis Inhibitors ; Antibodies, Monoclonal, Humanized ; VEGFA protein, human ; Vascular Endothelial Growth Factor A ; Ranibizumab (ZL1R02VT79)
Language	English
Publishing date	2015-03
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2408333-1
ISSN	1755-3768 ; 1755-375X
ISSN (online)	1755-3768
ISSN	1755-375X
DOI	10.1111/aos.12610
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Article: Cytokine mediated suppression of TF-1 apoptosis requires PI3K activation and inhibition of Bim expression.

Rosas, Marcela / Birkenkamp, Kim U / Lammers, Jan-Willem J / Koenderman, Leo / Coffer, Paul J

FEBS letters

2005 Volume 579, Issue 1, Page(s) 191–198

Abstract: Phosphatidylinositol 3-kinase (PI3K) and its effector protein kinase B (PKB/c-akt) have been implicated as critical mediators of cytokine-induced survival signals. In this study, we have utilized an IL-5 dependent hematopoietic cell line (TF-1) to ... ...

Abstract	Phosphatidylinositol 3-kinase (PI3K) and its effector protein kinase B (PKB/c-akt) have been implicated as critical mediators of cytokine-induced survival signals. In this study, we have utilized an IL-5 dependent hematopoietic cell line (TF-1) to investigate the signaling events involved in cytokine-dependent erythroblast survival. We demonstrate that IL-5 rescues TF-1 cells from apoptosis through a PI3K/PKB-dependent signaling pathway. Cytokine-withdrawal leads to activation of the Forkhead transcription factor FOXO3a and subsequent expression of the pro-apoptotic Bcl-2 family member Bim. Bim is itself sufficient to induce apoptosis in these cells. Importantly, activation of an inducible active FOXO3a mutant is alone sufficient for upregulation of Bim expression and induction of apoptosis. These data define a mechanism by which survival factors inhibit the default apoptotic pathway and can regulate TF-1 erythroblast survival.
MeSH term(s)	Apoptosis ; Apoptosis Regulatory Proteins ; Bcl-2-Like Protein 11 ; Carrier Proteins/metabolism ; Caspase 3 ; Caspase 7 ; Caspases/metabolism ; Cell Line ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Erythroblasts/metabolism ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Glycogen Synthase Kinase 3/physiology ; Humans ; Interleukin-5/physiology ; Membrane Proteins/metabolism ; Mutation/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Proto-Oncogene Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; BCL2L11 protein, human ; Bcl-2-Like Protein 11 ; Carrier Proteins ; DNA-Binding Proteins ; FOXO1 protein, human ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Interleukin-5 ; Membrane Proteins ; Proto-Oncogene Proteins ; Transcription Factors ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; CASP3 protein, human (EC 3.4.22.-) ; CASP7 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 7 (EC 3.4.22.-) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2005-01-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2004.11.074
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Article: Chronic protein kinase B (PKB/c-akt) activation leads to apoptosis induced by oxidative stress-mediated Foxo3a transcriptional up-regulation.

van Gorp, Ankie G M / Pomeranz, Karen M / Birkenkamp, Kim U / Hui, Rosaline C-Y / Lam, Eric W-F / Coffer, Paul J

Cancer research

2006 Volume 66, Issue 22, Page(s) 10760–10769

Abstract: Increased protein kinase B (PKB; c-Akt) activation is a hallmark of diverse neoplasias providing both proliferative and antiapoptotic survival signals. In this study, we investigated the effect of chronic PKB activation on cellular survival and ... ...

Abstract	Increased protein kinase B (PKB; c-Akt) activation is a hallmark of diverse neoplasias providing both proliferative and antiapoptotic survival signals. In this study, we investigated the effect of chronic PKB activation on cellular survival and proliferation using cytokine-dependent bone marrow-derived Ba/F3 cells, in which PKBalpha activation can be directly, and specifically, induced by addition of 4-hydroxytamoxifen (4-OHT). Direct activation of PKB rescued Ba/F3 cells from cytokine withdrawal-induced apoptosis; however, surprisingly, these antiapoptotic effects were short lived, cells only being protected for up to 48 hours. We observed that activation of PKB in survival factor-deprived cells led to a dramatic increase of Foxo3a on both the transcriptional and protein level leading to expression of its transcriptional targets Bim and p27(kip1). High levels of PKB activity result in increased aerobic glycolysis and mitochondrial activity resulting in overproduction of reactive oxygen species. To determine whether oxidative stress might itself be responsible for Foxo3a up-regulation, we utilized hydrogen peroxide (H(2)O(2)) as an artificial inducer of oxidative stress and N-acetylcysteine (NAC), a thiol-containing radical oxygen scavenger. Addition of NAC to the culture medium prolonged the life span of cells treated with 4-OHT and prevented the up-regulation of Foxo3a protein levels caused by PKB activation. Conversely, treatment of Ba/F3 cells with H(2)O(2) caused an increase of Foxo3a on both transcriptional and protein levels, suggesting that deregulated PKB activation leads to oxidative stress resulting in Foxo3a up-regulation and subsequently cell death. Taken together, our data provide novel insights into the molecular consequences of uncontrolled PKB activation.
MeSH term(s)	Animals ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/biosynthesis ; Apoptosis Regulatory Proteins/genetics ; Bcl-2-Like Protein 11 ; Cyclin-Dependent Kinase Inhibitor p27/biosynthesis ; Cyclin-Dependent Kinase Inhibitor p27/genetics ; Enzyme Activation ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/biosynthesis ; Forkhead Transcription Factors/genetics ; Membrane Proteins/biosynthesis ; Membrane Proteins/genetics ; Mice ; Oxidative Stress/physiology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Transcription, Genetic ; Up-Regulation
Chemical Substances	Apoptosis Regulatory Proteins ; Bcl-2-Like Protein 11 ; Bcl2l11 protein, mouse ; Cdkn1b protein, mouse ; Forkhead Box Protein O3 ; Forkhead Transcription Factors ; FoxO3 protein, mouse ; Membrane Proteins ; Proto-Oncogene Proteins ; Reactive Oxygen Species ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2006-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-06-1111
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Article ; Online: An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer.

Lindskrog, Sia Viborg / Prip, Frederik / Lamy, Philippe / Taber, Ann / Groeneveld, Clarice S / Birkenkamp-Demtröder, Karin / Jensen, Jørgen Bjerggaard / Strandgaard, Trine / Nordentoft, Iver / Christensen, Emil / Sokac, Mateo / Birkbak, Nicolai J / Maretty, Lasse / Hermann, Gregers G / Petersen, Astrid C / Weyerer, Veronika / Grimm, Marc-Oliver / Horstmann, Marcus / Sjödahl, Gottfrid /

Höglund, Mattias / Steiniche, Torben / Mogensen, Karin / de Reyniès, Aurélien / Nawroth, Roman / Jordan, Brian / Lin, Xiaoqi / Dragicevic, Dejan / Ward, Douglas G / Goel, Anshita / Hurst, Carolyn D / Raman, Jay D / Warrick, Joshua I / Segersten, Ulrika / Sikic, Danijel / van Kessel, Kim E M / Maurer, Tobias / Meeks, Joshua J / DeGraff, David J / Bryan, Richard T / Knowles, Margaret A / Simic, Tatjana / Hartmann, Arndt / Zwarthoff, Ellen C / Malmström, Per-Uno / Malats, Núria / Real, Francisco X / Dyrskjøt, Lars

Nature communications

2021 Volume 12, Issue 1, Page(s) 2301

Abstract: The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). ... ...

Abstract	The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
MeSH term(s)	Aged ; BCG Vaccine/administration & dosage ; Biomarkers, Tumor/genetics ; Carcinoma, Transitional Cell/genetics ; Carcinoma, Transitional Cell/immunology ; Carcinoma, Transitional Cell/mortality ; Carcinoma, Transitional Cell/therapy ; Chromosomal Instability ; Cystectomy/methods ; Denmark/epidemiology ; Female ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Genomics ; Humans ; Kaplan-Meier Estimate ; Male ; Mutation ; Neoplasm Recurrence, Local/epidemiology ; Neoplasm Recurrence, Local/genetics ; Prognosis ; Progression-Free Survival ; RNA-Seq ; Urinary Bladder/immunology ; Urinary Bladder/pathology ; Urinary Bladder/surgery ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/immunology ; Urinary Bladder Neoplasms/mortality ; Urinary Bladder Neoplasms/therapy
Chemical Substances	BCG Vaccine ; Biomarkers, Tumor
Language	English
Publishing date	2021-04-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-22465-w
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Article: FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity.

Dijkers, Pascale F / Birkenkamp, Kim U / Lam, Eric W-F / Thomas, N Shaun B / Lammers, Jan-Willem J / Koenderman, Leo / Coffer, Paul J

The Journal of cell biology

2002 Volume 156, Issue 3, Page(s) 531–542

Abstract: Survival signals elicited by cytokines include the activation of phosphatidylinositol 3-kinase (PI3K), which in turn promotes the activation of protein kinase B (PKB). Recently, PKB has been demonstrated to phosphorylate and inactivate forkhead ... ...

Abstract	Survival signals elicited by cytokines include the activation of phosphatidylinositol 3-kinase (PI3K), which in turn promotes the activation of protein kinase B (PKB). Recently, PKB has been demonstrated to phosphorylate and inactivate forkhead transcription factor FKHR-L1, a potent inducer of apoptosis. To explore the mechanisms underlying the induction of apoptosis after cytokine withdrawal or FKHR-L1 activation, we used a cell line in which FKHR-L1 activity could be specifically induced. Both cytokine withdrawal and FKHR-L1 activation induced apoptosis, which was preceded by an upregulation in p27KIP1 and a concomitant decrease in cells entering the cell cycle. Induction of apoptosis by both cytokine withdrawal and activation of FKHR-L1 correlated with the disruption of mitochondrial membrane integrity and cytochrome c release. This was preceded by upregulation of the pro-apoptotic Bcl-2 family member Bim. Ectopic expression of an inhibitory mutant of FKHR-L1 substantially reduced the levels of apoptosis observed after cytokine withdrawal. Activation of PKB alone was sufficient to promote cell survival, as measured by maintenance of mitochondrial integrity and the resultant inhibition of effector caspases. Furthermore, hematopoietic stem cells isolated from Bim-/- mice exhibited reduced levels of apoptosis upon inhibition of PI3K/PKB signaling. These data demonstrate that activation of FKHR-L1 alone can recapitulate all known elements of the apoptotic program normally induced by cytokine withdrawal. Thus PI3K/PKB--mediated inhibition of this transcription factor likely provides an important mechanism by which survival factors act to prevent programmed cell death.
MeSH term(s)	Animals ; Annexin A5/metabolism ; Apoptosis Regulatory Proteins ; Bcl-2-Like Protein 11 ; Carrier Proteins/metabolism ; Caspases/metabolism ; Cell Cycle/drug effects ; Cell Cycle/physiology ; Cell Cycle Proteins/metabolism ; Cell Death/drug effects ; Cell Death/physiology ; Cell Survival/drug effects ; Cell Survival/physiology ; Cyclin-Dependent Kinase Inhibitor p27 ; Cytochrome c Group/metabolism ; Cytokines/deficiency ; Cytokines/pharmacology ; DNA-Binding Proteins/metabolism ; Female ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Male ; Membrane Potentials/physiology ; Membrane Proteins ; Mice ; Mice, Knockout ; Mitochondria/drug effects ; Mitochondria/metabolism ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; Protein-Serine-Threonine Kinases ; Proteins/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Annexin A5 ; Apoptosis Regulatory Proteins ; Bcl-2-Like Protein 11 ; Bcl2l11 protein, mouse ; Carrier Proteins ; Cdkn1b protein, mouse ; Cell Cycle Proteins ; Cytochrome c Group ; Cytokines ; DNA-Binding Proteins ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Foxo1 protein, mouse ; Membrane Proteins ; Proteins ; Proto-Oncogene Proteins ; Transcription Factors ; Tumor Suppressor Proteins ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Parp1 protein, mouse (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2002-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.200108084
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Article: FOXO3a Induces Differentiation of Bcr-Abl-transformed Cells through Transcriptional Down-regulation of Id1

Birkenkamp, Kim U / Essafi, Abdelkader / van der Vos, Kristan E / da Costa, Marco / Hui, Rosaline C.-Y / Holstege, Frank / Koenderman, Leo / Lam, Eric W.-F / Coffer, Paul J

Journal of biological chemistry. 2007 Jan. 26, v. 282, no. 4

2007

Abstract: Leukemic transformation often requires activation of protein kinase B (PKB/c-Akt) and is characterized by increased proliferation, decreased apoptosis, and a differentiation block. PKB phosphorylates and inactivates members of the FOXO subfamily of ... ...

Abstract	Leukemic transformation often requires activation of protein kinase B (PKB/c-Akt) and is characterized by increased proliferation, decreased apoptosis, and a differentiation block. PKB phosphorylates and inactivates members of the FOXO subfamily of Forkhead transcription factors. It has been suggested that hyperactivation of PKB maintains the leukemic phenotype through actively repressing FOXO-mediated regulation of specific genes. We have found expression of the transcriptional repressor Id1 (inhibitor of DNA binding 1) to be abrogated by FOXO3a activation. Inhibition of PKB activation or growth factor deprivation also resulted in strong down-regulation of Id1 promoter activity, Id1 mRNA, and protein expression. Id1 is highly expressed in Bcr-Abl-transformed K562 cells, correlating with high PKB activation and FOXO3a phosphorylation. Inhibition of Bcr-Abl by the chemical inhibitor STI571 resulted in activation of FOXO3a and down-regulation of Id1 expression. By performing chromatin immunoprecipitation assays and promoter-mutation analysis, we demonstrate that FOXO3a acts as a transcriptional repressor by directly binding to the Id1 promoter. STI571 treatment, or expression of constitutively active FOXO3a, resulted in erythroid differentiation of K562 cells, which was inhibited by ectopic expression of Id1. Taken together our data strongly suggest that high expression of Id1, through PKB-mediated inhibition of FOXO3a, is critical for maintenance of the leukemic phenotype.
Language	English
Dates of publication	2007-0126
Size	p. 2211-2220.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional down-regulation of Id1.

Birkenkamp, Kim U / Essafi, Abdelkader / van der Vos, Kristan E / da Costa, Marco / Hui, Rosaline C-Y / Holstege, Frank / Koenderman, Leo / Lam, Eric W-F / Coffer, Paul J

The Journal of biological chemistry

2006 Volume 282, Issue 4, Page(s) 2211–2220

Abstract	Leukemic transformation often requires activation of protein kinase B (PKB/c-Akt) and is characterized by increased proliferation, decreased apoptosis, and a differentiation block. PKB phosphorylates and inactivates members of the FOXO subfamily of Forkhead transcription factors. It has been suggested that hyperactivation of PKB maintains the leukemic phenotype through actively repressing FOXO-mediated regulation of specific genes. We have found expression of the transcriptional repressor Id1 (inhibitor of DNA binding 1) to be abrogated by FOXO3a activation. Inhibition of PKB activation or growth factor deprivation also resulted in strong down-regulation of Id1 promoter activity, Id1 mRNA, and protein expression. Id1 is highly expressed in Bcr-Abl-transformed K562 cells, correlating with high PKB activation and FOXO3a phosphorylation. Inhibition of Bcr-Abl by the chemical inhibitor STI571 resulted in activation of FOXO3a and down-regulation of Id1 expression. By performing chromatin immunoprecipitation assays and promoter-mutation analysis, we demonstrate that FOXO3a acts as a transcriptional repressor by directly binding to the Id1 promoter. STI571 treatment, or expression of constitutively active FOXO3a, resulted in erythroid differentiation of K562 cells, which was inhibited by ectopic expression of Id1. Taken together our data strongly suggest that high expression of Id1, through PKB-mediated inhibition of FOXO3a, is critical for maintenance of the leukemic phenotype.
MeSH term(s)	Animals ; Base Sequence ; Bone Marrow Cells/metabolism ; Bone Marrow Cells/pathology ; Cell Differentiation/genetics ; Cell Line, Transformed ; Cell Transformation, Neoplastic ; Down-Regulation ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation, Neoplastic ; Genes, abl ; Humans ; Inhibitor of Differentiation Protein 1/genetics ; Inhibitor of Differentiation Protein 1/metabolism ; K562 Cells ; Leukemia/genetics ; Leukemia/pathology ; Mice ; Molecular Sequence Data ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-akt/metabolism ; Transcription, Genetic
Chemical Substances	Forkhead Box Protein O3 ; Forkhead Transcription Factors ; FoxO3 protein, mouse ; Idb1 protein, mouse ; Inhibitor of Differentiation Protein 1 ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2006-11-27
Publishing country	United States
Document type	Journal Article ; 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.M606669200
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Article: Bcl-2 prevents loss of mitochondria in CCCP-induced apoptosis.

de Graaf, Aniek O / van den Heuvel, Lambert P / Dijkman, Henry B P M / de Abreu, Ronney A / Birkenkamp, Kim U / de Witte, Theo / van der Reijden, Bert A / Smeitink, Jan A M / Jansen, Joop H

Experimental cell research

2004 Volume 299, Issue 2, Page(s) 533–540

Abstract: Bcl-2 family proteins regulate apoptosis at the level of mitochondria. To examine the mechanism of Bcl-2 function, we investigated the effects of the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) on two hematopoietic cell lines and Bcl-2 ... ...

Abstract	Bcl-2 family proteins regulate apoptosis at the level of mitochondria. To examine the mechanism of Bcl-2 function, we investigated the effects of the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) on two hematopoietic cell lines and Bcl-2 overexpressing transfectants. CCCP directly interferes with mitochondrial function and induces apoptosis. We show that Bcl-2 inhibits apoptosis and that the antiapoptotic effect of Bcl-2 takes place upstream of caspase activation and nuclear changes associated with apoptosis, since these were markedly inhibited in cells overexpressing Bcl-2. Bcl-2 does not prevent the decrease in mitochondrial membrane potential nor the alterations in cellular ATP content induced by CCCP in FL5.12 and Jurkat cells. A higher number of mitochondria was observed in untreated Bcl-2 transfected cells compared to parental cells, as shown by electron microscopy. Exposure to CCCP induced a dramatic decrease in the number of mitochondria and severely disrupted mitochondrial ultrastructure, with apparent swelling and loss of cristae in parental cells. Bcl-2 clearly diminished the disruption of mitochondrial structure and preserved a higher number of mitochondria. These data suggest that CCCP induces apoptosis by structural disruption of mitochondria and that Bcl-2 prevents apoptosis and mitochondrial degeneration by preserving mitochondrial integrity.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Apoptosis/drug effects ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology ; Caspases/metabolism ; Cell Nucleus ; Enzyme Activation/drug effects ; Humans ; Jurkat Cells ; Lymphoma, B-Cell/metabolism ; Lymphoma, B-Cell/pathology ; Membrane Potentials/drug effects ; Mice ; Mitochondria/drug effects ; Mitochondria/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Proto-Oncogene Proteins c-bcl-2/pharmacology
Chemical Substances	Proto-Oncogene Proteins c-bcl-2 ; Carbonyl Cyanide m-Chlorophenyl Hydrazone (555-60-2) ; Adenosine Triphosphate (8L70Q75FXE) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2004-10-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2004.06.024
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Article: FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism.

Fernández de Mattos, Silvia / Essafi, Abdelkader / Soeiro, Inês / Pietersen, Alexandra M / Birkenkamp, Kim U / Edwards, Corinne S / Martino, Anthony / Nelson, Brad H / Francis, Julia M / Jones, Marius C / Brosens, Jan J / Coffer, Paul J / Lam, Eric W-F

Molecular and cellular biology

2004 Volume 24, Issue 22, Page(s) 10058–10071

Abstract: Cell cycle arrest by FoxO transcription factors involves transcriptional repression of cyclin D, although the exact mechanism remains unclear. In this study, we used the BCR-ABL-expressing cell line BV173 as a model system to investigate the mechanisms ... ...

Abstract	Cell cycle arrest by FoxO transcription factors involves transcriptional repression of cyclin D, although the exact mechanism remains unclear. In this study, we used the BCR-ABL-expressing cell line BV173 as a model system to investigate the mechanisms whereby FoxO3a regulates cyclin D2 expression. Inhibition of BCR-ABL by STI571 results in down-regulation of cyclin D2 expression, activation of FoxO3a activity, and up-regulation of BCL6 expression. Using reporter gene assays, we demonstrate that STI571, FoxO3a, and BCL6 can repress cyclin D2 transcription through a STAT5/BCL6 site located within the cyclin D2 promoter. We propose that BCR-ABL inhibition leads to FoxO3a activation, which in turn induces the expression of BCL6, culminating in the repression of cyclin D2 transcription through this STAT5/BCL6 site. This process was verified by mobility shift and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to accumulation of BCL6 and down-regulation of cyclin D2 at protein and mRNA levels. Furthermore, silencing of FoxO3a and BCL6 in BCR-ABL-expressing cells abolishes STI571-mediated effects on cyclin D2. This report establishes the signaling events whereby BCR-ABL signals are relayed to cyclin D2 to mediate cell cycle progression and defines a potential mechanism by which FoxO proteins regulate cyclin D2 expression.
MeSH term(s)	Base Sequence ; Benzamides ; Binding Sites/genetics ; Cell Line ; Cyclin D2 ; Cyclins/genetics ; Cyclins/metabolism ; DNA, Complementary/genetics ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Fusion Proteins, bcr-abl/antagonists & inhibitors ; Fusion Proteins, bcr-abl/genetics ; Fusion Proteins, bcr-abl/metabolism ; Humans ; Imatinib Mesylate ; Milk Proteins/genetics ; Milk Proteins/metabolism ; Nuclear Proteins/metabolism ; Phosphorylation ; Piperazines/pharmacology ; Promoter Regions, Genetic ; Protein Binding ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-bcl-6 ; Pyrimidines/pharmacology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; STAT5 Transcription Factor ; Signal Transduction ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic/drug effects
Chemical Substances	BCL6 protein, human ; Benzamides ; CCND2 protein, human ; Cyclin D2 ; Cyclins ; DNA, Complementary ; DNA-Binding Proteins ; FOXO1 protein, human ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Milk Proteins ; Nuclear Proteins ; Piperazines ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-bcl-6 ; Pyrimidines ; RNA, Messenger ; RNA, Small Interfering ; STAT5 Transcription Factor ; Trans-Activators ; Transcription Factors ; Imatinib Mesylate (8A1O1M485B) ; Fusion Proteins, bcr-abl (EC 2.7.10.2)
Language	English
Publishing date	2004-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.24.22.10058-10071.2004
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