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Article: Hypoxia-inducible factors as essential regulators of inflammation.

Imtiyaz, Hongxia Z / Simon, M Celeste

Current topics in microbiology and immunology

2010 Volume 345, Page(s) 105–120

Abstract: Myeloid cells provide important functions in low oxygen (O(2)) environments created by pathophysiological conditions, including sites of infection, inflammation, tissue injury, and solid tumors. Hypoxia-inducible factors (HIFs) are principle regulators ... ...

Abstract	Myeloid cells provide important functions in low oxygen (O(2)) environments created by pathophysiological conditions, including sites of infection, inflammation, tissue injury, and solid tumors. Hypoxia-inducible factors (HIFs) are principle regulators of hypoxic adaptation, regulating gene expression involved in glycolysis, erythropoiesis, angiogenesis, proliferation, and stem cell function under low O(2). Interestingly, increasing evidence accumulated over recent years suggests an additional important regulatory role for HIFs in inflammation. In macrophages, HIFs not only regulate glycolytic energy generation, but also optimize innate immunity, control pro-inflammatory gene expression, mediate bacterial killing and influence cell migration. In neutrophils, HIF-1α promotes survival under O(2)-deprived conditions and mediates blood vessel extravasation by modulating β (2) integrin expression. Additionally, HIFs contribute to inflammatory functions in various other components of innate immunity, such as dendritic cells, mast cells, and epithelial cells. This review will dissect the role of each HIF isoform in myeloid cell function and discuss their impact on acute and chronic inflammatory disorders. Currently, intensive studies are being conducted to illustrate the connection between inflammation and tumorigenesis. Detailed investigation revealing interaction between microenvironmental factors such as hypoxia and immune cells is needed. We will also discuss how hypoxia and HIFs control properties of tumor-associated macrophages and their relationship to tumor formation and progression.
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Transcription Factors/physiology ; Cell Hypoxia ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/physiology ; Inflammation/etiology ; Macrophages/physiology ; Neoplasms/pathology
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; Hypoxia-Inducible Factor 1, alpha Subunit ; endothelial PAS domain-containing protein 1 (1B37H0967P)
Language	English
Publishing date	2010-05-20
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	0070-217X
ISSN	0070-217X
DOI	10.1007/82_2010_74
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Article: Structural requirements for signal-induced target binding of FADD determined by functional reconstitution of FADD deficiency.

Imtiyaz, Hongxia Z / Zhang, Yuhang / Zhang, Jianke

The Journal of biological chemistry

2005 Volume 280, Issue 36, Page(s) 31360–31367

Abstract: FADD is a key adaptor modulating several signaling pathways such as apoptosis induced by Fas (CD95) and tumor necrosis factor receptor 1, and cell proliferation induced by mitogens. Whereas mutations in Fas disrupt its binding to FADD and cause ... ...

Abstract	FADD is a key adaptor modulating several signaling pathways such as apoptosis induced by Fas (CD95) and tumor necrosis factor receptor 1, and cell proliferation induced by mitogens. Whereas mutations in Fas disrupt its binding to FADD and cause autoimmune lymphoproliferative (lpr) syndromes, a FADD deficiency blocks embryonic development in mice. To delineate the multifunction of FADD in vivo, we performed functional reconstitution analysis by introducing wild type and mutant FADD into FADD-/- cells or FADD-/- mice lacking the endogenous FADD. An lpr-like FADD mutant, V121N, was reported previously as being defective in Fas binding in vitro. However, we found that in mice V121N can bind to Fas and is functional in signaling apoptosis. Unexpectedly, this lpr-like mutant FADD failed to support mouse development, indicating that the death domain of FADD has an additional function required for embryogenesis, which is independent of that required for receptor-induced apoptosis. Further mutagenesis was targeted at charged residues in the FADD death domain, presumably mediating electrostatic interactions with Fas. We showed that the target binding and apoptosis signaling functions of FADD were not affected when mutations were introduced to a majority of the charged residues. In one exception, replacing arginine 117 with an uncharged residue disrupted target binding and apoptosis signaling, but restoring the positive charge at position 117 failed to reconstitute the FADD function. Therefore, in vivo target binding of FADD involves an additional mechanism distinct from electrostatic interaction.
MeSH term(s)	Adaptor Proteins, Signal Transducing/chemistry ; Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Amino Acid Sequence ; Animals ; Apoptosis/genetics ; Fas-Associated Death Domain Protein ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Mutation ; Protein Binding/genetics ; Protein Structure, Tertiary ; Signal Transduction/genetics ; TNF Receptor-Associated Death Domain Protein ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism ; fas Receptor/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Fadd protein, mouse ; Fas-Associated Death Domain Protein ; TNF Receptor-Associated Death Domain Protein ; Tradd protein, mouse ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ; fas Receptor
Language	English
Publishing date	2005-07-11
Publishing country	United States
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	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M504138200
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Article: The Death Domain of FADD Is Essential for Embryogenesis, Lymphocyte Development, and Proliferation

Imtiyaz, Hongxia Z / Zhou, Xiaohui / Zhang, Haibing / Chen, Dehua / Hu, Taishan / Zhang, Jianke

Journal of biological chemistry. 2009 Apr. 10, v. 284, no. 15

2009

Abstract: The Fas-associated death domain-containing protein (FADD) is an adaptor for relaying apoptotic signals initiated by death receptors such as Fas. Whereas a lack of death receptors has no effect on mouse development, FADD deficiency results in early ... ...

Abstract	The Fas-associated death domain-containing protein (FADD) is an adaptor for relaying apoptotic signals initiated by death receptors such as Fas. Whereas a lack of death receptors has no effect on mouse development, FADD deficiency results in early embryonic lethality, indicating that FADD has additional functions independent of death receptors. We have previously shown that conditional deletion of FADD not only impairs apoptosis but also leads to defective lymphocyte proliferation. The non-apoptotic signaling mediated by FADD remains poorly understood. Earlier studies have suggested that FADD carboxyl terminal serine phosphorylation likely plays a role in FADD-mediated proliferation signaling in T cells. The FADD death domain is presumably only required for apoptotic signaling, as it interacts with death receptors which are dispensable during embryonic development and lymphocyte proliferation. To test this hypothesis, we have performed mutational analyses of the FADD death domain and identified a mutant, R117Q, which lacks binding to Fas and, thus, is incapable of apoptotic signaling in cell lines. Unexpectedly, this death domain point mutation disrupted mouse embryonic development as shown by in vivo functional reconstitution analyses. Interestingly, a second FADD death domain mutant, V121N, retained normal Fas binding and apoptotic signaling ability but also failed to support mouse development. Furthermore, lymphocyte proliferation responses were impaired by V121N. This reverse genetic study has revealed a previously unappreciated role of the FADD death domain, which likely functions as a molecular switch regulating two distinct signals leading to apoptosis and cell proliferation and is critical for embryogenesis, lymphocyte development, and proliferation.
Language	English
Dates of publication	2009-0410
Size	p. 9917-9926.
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: The death domain of FADD is essential for embryogenesis, lymphocyte development, and proliferation.

Imtiyaz, Hongxia Z / Zhou, Xiaohui / Zhang, Haibing / Chen, Dehua / Hu, Taishan / Zhang, Jianke

The Journal of biological chemistry

2009 Volume 284, Issue 15, Page(s) 9917–9926

Abstract	The Fas-associated death domain-containing protein (FADD) is an adaptor for relaying apoptotic signals initiated by death receptors such as Fas. Whereas a lack of death receptors has no effect on mouse development, FADD deficiency results in early embryonic lethality, indicating that FADD has additional functions independent of death receptors. We have previously shown that conditional deletion of FADD not only impairs apoptosis but also leads to defective lymphocyte proliferation. The non-apoptotic signaling mediated by FADD remains poorly understood. Earlier studies have suggested that FADD carboxyl terminal serine phosphorylation likely plays a role in FADD-mediated proliferation signaling in T cells. The FADD death domain is presumably only required for apoptotic signaling, as it interacts with death receptors which are dispensable during embryonic development and lymphocyte proliferation. To test this hypothesis, we have performed mutational analyses of the FADD death domain and identified a mutant, R117Q, which lacks binding to Fas and, thus, is incapable of apoptotic signaling in cell lines. Unexpectedly, this death domain point mutation disrupted mouse embryonic development as shown by in vivo functional reconstitution analyses. Interestingly, a second FADD death domain mutant, V121N, retained normal Fas binding and apoptotic signaling ability but also failed to support mouse development. Furthermore, lymphocyte proliferation responses were impaired by V121N. This reverse genetic study has revealed a previously unappreciated role of the FADD death domain, which likely functions as a molecular switch regulating two distinct signals leading to apoptosis and cell proliferation and is critical for embryogenesis, lymphocyte development, and proliferation.
MeSH term(s)	Amino Acid Sequence ; Animals ; Apoptosis ; Cell Proliferation ; Fas-Associated Death Domain Protein/metabolism ; Gene Expression Regulation, Developmental ; Lymphocytes/cytology ; Mice ; Molecular Sequence Data ; Phosphorylation ; Point Mutation ; Protein Binding ; Protein Structure, Tertiary ; Sequence Homology, Amino Acid ; T-Lymphocytes/metabolism
Chemical Substances	Fas-Associated Death Domain Protein
Language	English
Publishing date	2009-02-09
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.M900249200
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Article ; Online: Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and dysfunctional tumor microvasculature.

Rybinski, Katherine / Imtiyaz, Hongxia Z / Mittica, Barrie / Drozdowski, Brian / Fulmer, James / Furuuchi, Keiji / Fernando, Shawn / Henry, Marianne / Chao, Qimin / Kline, Brad / Albone, Earl / Wustner, Jason / Lin, JianMin / Nicolaides, Nicholas C / Grasso, Luigi / Zhou, Yuhong

Oncotarget

2016 Volume 6, Issue 28, Page(s) 25429–25440

Abstract: Over-expression of endosialin/CD248 (herein referred to as CD248) has been associated with increased tumor microvasculature in various tissue origins which makes it an attractive anti-angiogenic target. In an effort to target CD248, we have generated a ... ...

Abstract	Over-expression of endosialin/CD248 (herein referred to as CD248) has been associated with increased tumor microvasculature in various tissue origins which makes it an attractive anti-angiogenic target. In an effort to target CD248, we have generated a human CD248 knock-in mouse line and MORAb-004, the humanized version of the mouse anti-human CD248 antibody Fb5. Here, we report that MORAb-004 treatment significantly impacted syngeneic tumor growth and tumor metastasis in the human CD248 knock-in mice. In comparison with untreated tumors, MORAb-004 treated tumors displayed overall shortened and distorted blood vessels. Immunofluorescent staining of tumor sections revealed drastically more small and dysfunctional vessels in the treated tumors. The CD248 levels on cell surfaces of neovasculature pericytes were significantly reduced due to its internalization. This reduction of CD248 was also accompanied by reduced α-SMA expression, depolarization of pericytes and endothelium, and ultimately dysfunctional microvessels. These results suggest that MORAb-004 reduced CD248 on pericytes, impaired tumor microvasculature maturation and ultimately suppressed tumor development.
MeSH term(s)	Actins/metabolism ; Angiogenesis Inhibitors/metabolism ; Angiogenesis Inhibitors/pharmacology ; Animals ; Antibodies, Monoclonal, Humanized/metabolism ; Antibodies, Monoclonal, Humanized/pharmacology ; Antigens, CD/genetics ; Antigens, CD/immunology ; Antigens, CD/metabolism ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/immunology ; Antigens, Neoplasm/metabolism ; Biological Transport ; Carcinoma, Lewis Lung/blood supply ; Carcinoma, Lewis Lung/drug therapy ; Carcinoma, Lewis Lung/genetics ; Carcinoma, Lewis Lung/immunology ; Carcinoma, Lewis Lung/metabolism ; Carcinoma, Lewis Lung/pathology ; Cell Movement/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Endothelial Cells/immunology ; Endothelial Cells/metabolism ; Female ; Humans ; Male ; Melanoma, Experimental/blood supply ; Melanoma, Experimental/drug therapy ; Melanoma, Experimental/genetics ; Melanoma, Experimental/immunology ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/pathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Microvessels/drug effects ; Microvessels/immunology ; Microvessels/metabolism ; Microvessels/pathology ; Neoplasm Metastasis ; Neovascularization, Pathologic ; Pericytes/drug effects ; Pericytes/immunology ; Pericytes/metabolism ; Pericytes/pathology ; RNA Interference ; Time Factors ; Transfection ; Tumor Burden/drug effects
Chemical Substances	Acta2 protein, mouse ; Actins ; Angiogenesis Inhibitors ; Antibodies, Monoclonal, Humanized ; Antigens, CD ; Antigens, Neoplasm ; CD248 protein, human ; MORAb-004 (0M2XT000YC)
Language	English
Publishing date	2016-06-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.4559
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Article ; Online: Inhibition of hypoxia-inducible factors limits tumor progression in a mouse model of colorectal cancer.

Shay, Jessica E S / Imtiyaz, Hongxia Z / Sivanand, Sharanya / Durham, Amy C / Skuli, Nicolas / Hsu, Sarah / Mucaj, Vera / Eisinger-Mathason, T S Karin / Krock, Bryan L / Giannoukos, Dionysios N / Simon, M Celeste

Carcinogenesis

2014 Volume 35, Issue 5, Page(s) 1067–1077

Abstract: Hypoxia-inducible factors (HIFs) accumulate in both neoplastic and inflammatory cells within the tumor microenvironment and impact the progression of a variety of diseases, including colorectal cancer. Pharmacological HIF inhibition represents a novel ... ...

Abstract	Hypoxia-inducible factors (HIFs) accumulate in both neoplastic and inflammatory cells within the tumor microenvironment and impact the progression of a variety of diseases, including colorectal cancer. Pharmacological HIF inhibition represents a novel therapeutic strategy for cancer treatment. We show here that acriflavine (ACF), a naturally occurring compound known to repress HIF transcriptional activity, halts the progression of an autochthonous model of established colitis-associated colon cancer (CAC) in immunocompetent mice. ACF treatment resulted in decreased tumor number, size and advancement (based on histopathological scoring) of CAC. Moreover, ACF treatment corresponded with decreased macrophage infiltration and vascularity in colorectal tumors. Importantly, ACF treatment inhibited the hypoxic induction of M-CSFR, as well as the expression of the angiogenic factor (vascular endothelial growth factor), a canonical HIF target, with little to no impact on the Nuclear factor-kappa B pathway in bone marrow-derived macrophages. These effects probably explain the observed in vivo phenotypes. Finally, an allograft tumor model further confirmed that ACF treatment inhibits tumor growth through HIF-dependent mechanisms. These results suggest pharmacological HIF inhibition in multiple cell types, including epithelial and innate immune cells, significantly limits tumor growth and progression.
MeSH term(s)	Acriflavine/administration & dosage ; Acriflavine/pharmacology ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Aryl Hydrocarbon Receptor Nuclear Translocator/genetics ; Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Macrophages/drug effects ; Macrophages/metabolism ; Macrophages/pathology ; Mice ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/genetics ; Signal Transduction/drug effects ; Transcription, Genetic/drug effects ; Tumor Burden/drug effects ; Tumor Burden/genetics ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Hypoxia-Inducible Factor 1, alpha Subunit ; Aryl Hydrocarbon Receptor Nuclear Translocator (138391-32-9) ; Acriflavine (1T3A50395T)
Language	English
Publishing date	2014-01-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603134-1
ISSN	1460-2180 ; 0143-3334
ISSN (online)	1460-2180
ISSN	0143-3334
DOI	10.1093/carcin/bgu004
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Article: Conditional Fas-associated death domain protein (FADD): GFP knockout mice reveal FADD is dispensable in thymic development but essential in peripheral T cell homeostasis.

Zhang, Yuhang / Rosenberg, Stephen / Wang, Hanming / Imtiyaz, Hongxia Z / Hou, Ying-Ju / Zhang, Jianke

Journal of immunology (Baltimore, Md. : 1950)

2005 Volume 175, Issue 5, Page(s) 3033–3044

Abstract: Fas-associated death domain protein (FADD)/mediator of receptor-induced toxicity-1 is required for signaling induced by death receptors such as Fas. In earlier studies, FADD-deficient mice died in utero, and a FADD deficiency in embryonic stem cells ... ...

Abstract	Fas-associated death domain protein (FADD)/mediator of receptor-induced toxicity-1 is required for signaling induced by death receptors such as Fas. In earlier studies, FADD-deficient mice died in utero, and a FADD deficiency in embryonic stem cells inhibited T cell production in viable FADD-/- -->RAG-1-/- chimeras. To analyze the temporal requirement of FADD in the development and function in the T lineage, it is necessary to establish viable mutant mice producing detectable FADD-deficient T cells. We generated mice that express a functional FADD:GFP fusion gene reconstituting normal embryogenesis and lymphopoiesis in the absence of the endogenous FADD. Efficient T cell-specific deletion of FADD:GFP was achieved, as indicated by the presence of a high percentage of GFP-negative thymocytes and peripheral T cells in mice expressing Lck-Cre or CD4-Cre. Sorted GFP-negative thymocytes and peripheral T cells contained undetectable levels of FADD and were resistant to apoptosis induced by Fas, TNF, and TCR restimulation. These T cell-specific FADD-deficient mice contain normal thymocyte numbers, but fewer peripheral T cells. Purified peripheral FADD-deficient T cells failed to undergo extensive homeostatic expansion after adoptive transfer into lymphocyte-deficient hosts, and responded poorly to proliferation induced by ex vivo TCR stimulation. Furthermore, deletion of FADD in preactivated mature T cells using retrovirus-Cre resulted in no proliferation. These results demonstrate that FADD plays a dispensable role during thymocyte development, but is essential in maintaining peripheral T cell homeostasis and regulating both apoptotic and proliferation signals.
MeSH term(s)	Adaptor Proteins, Signal Transducing/physiology ; Animals ; Apoptosis ; Cells, Cultured ; Fas-Associated Death Domain Protein ; Green Fluorescent Proteins/genetics ; Homeostasis ; Integrases/physiology ; Lymphocyte Activation ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/physiology ; Mice ; Mice, Knockout ; Receptors, Antigen, T-Cell/physiology ; T-Lymphocytes/immunology ; T-Lymphocytes/physiology ; Thymus Gland/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Fadd protein, mouse ; Fas-Associated Death Domain Protein ; Receptors, Antigen, T-Cell ; Green Fluorescent Proteins (147336-22-9) ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2005-09-01
Publishing country	United States
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	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.175.5.3033
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Article ; Online: miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma.

Mathew, Lijoy K / Skuli, Nicolas / Mucaj, Vera / Lee, Samuel S / Zinn, Pascal O / Sathyan, Pratheesh / Imtiyaz, Hongxia Z / Zhang, Zhongfa / Davuluri, Ramana V / Rao, Shilpa / Venneti, Sriram / Lal, Priti / Lathia, Justin D / Rich, Jeremy N / Keith, Brian / Minn, Andy J / Simon, M Celeste

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

2013 Volume 111, Issue 1, Page(s) 291–296

Abstract: Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose ... ...

Abstract	Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose expression might regulate hypoxic GBM cell survival and growth. We determined that the expression of microRNA-218 (miR-218) is decreased significantly in highly necrotic mesenchymal GBM, and orthotopic tumor studies revealed that reduced miR-218 levels confer GBM resistance to chemotherapy. Importantly, miR-218 targets multiple components of receptor tyrosine kinase (RTK) signaling pathways, and miR-218 repression increases the abundance and activity of multiple RTK effectors. This elevated RTK signaling also promotes the activation of hypoxia-inducible factor (HIF), most notably HIF2α. We further show that RTK-mediated HIF2α regulation is JNK dependent, via jun proto-oncogene. Collectively, our results identify an miR-218-RTK-HIF2α signaling axis that promotes GBM cell survival and tumor angiogenesis, particularly in necrotic mesenchymal tumors.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Animals ; Antineoplastic Agents/pharmacology ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Brain Neoplasms/metabolism ; Cell Survival ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Glioblastoma/metabolism ; Humans ; Hypoxia ; Mesoderm/metabolism ; Mice ; Mice, Nude ; MicroRNAs/metabolism ; Middle Aged ; Necrosis ; Neoplasm Transplantation ; Neovascularization, Pathologic ; Oligonucleotide Array Sequence Analysis ; Receptor Protein-Tyrosine Kinases/metabolism ; Signal Transduction ; Young Adult
Chemical Substances	Antineoplastic Agents ; Basic Helix-Loop-Helix Transcription Factors ; MIRN218 microRNA, human ; MIRN218 microRNA, mouse ; MicroRNAs ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2013-12-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1314341111
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Article: The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells.

Imtiyaz, Hongxia Z / Rosenberg, Stephen / Zhang, Yuhang / Rahman, Ziaur S M / Hou, Ying-Ju / Manser, Tim / Zhang, Jianke

Journal of immunology (Baltimore, Md. : 1950)

2006 Volume 176, Issue 11, Page(s) 6852–6861

Abstract: The Fas-associated death domain protein (FADD)/Mort1 is a signaling adaptor protein which mediates the activation of caspase 8 during death receptor-induced apoptosis. Disruption of FADD in germ cells results in death receptor-independent embryonic ... ...

Abstract	The Fas-associated death domain protein (FADD)/Mort1 is a signaling adaptor protein which mediates the activation of caspase 8 during death receptor-induced apoptosis. Disruption of FADD in germ cells results in death receptor-independent embryonic lethality in mice. Previous studies indicated that in addition to its function in apoptosis, FADD is also required in peripheral T cell homeostasis and TCR-induced proliferative responses. In this report, we generated B cell-specific FADD-deficient mice and showed that deletion of FADD at the pro-B cell stage had minor effects on B cell development in the bone marrow, and resulted in increased splenic and lymph node B cell numbers and decreased peritoneal B1 cell numbers. As in T cells, a FADD deficiency inhibited Fas-induced apoptosis in B cells. However, B cell-proliferative responses induced by stimulation of the BCR and CD40 using anti-IgM or anti-CD40 Abs were unaffected by the absence of FADD. Further analyses revealed that FADD-deficient B cells were defective in proliferative responses induced by treatments with dsRNA and LPS which stimulate TLR3 and TLR4, respectively. Therefore, in addition to its apoptotic function, FADD also plays a role in TLR3- and TLR4-induced proliferative responses in B cells.
MeSH term(s)	Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/physiology ; Animals ; Antigens, Differentiation, B-Lymphocyte/biosynthesis ; Apoptosis/immunology ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Cell Proliferation ; Cells, Cultured ; Epitopes, B-Lymphocyte/immunology ; Fas-Associated Death Domain Protein ; Immunoglobulin D/blood ; Immunoglobulin M/blood ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Signal Transduction/genetics ; Signal Transduction/immunology ; Toll-Like Receptor 3/physiology ; Toll-Like Receptor 4/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antigens, Differentiation, B-Lymphocyte ; Epitopes, B-Lymphocyte ; Fadd protein, mouse ; Fas-Associated Death Domain Protein ; Immunoglobulin D ; Immunoglobulin M ; Lipopolysaccharides ; Tlr4 protein, mouse ; Toll-Like Receptor 3 ; Toll-Like Receptor 4
Language	English
Publishing date	2006-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
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.176.11.6852
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Article ; Online: Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation.

Imtiyaz, Hongxia Z / Williams, Emily P / Hickey, Michele M / Patel, Shetal A / Durham, Amy C / Yuan, Li-Jun / Hammond, Rachel / Gimotty, Phyllis A / Keith, Brian / Simon, M Celeste

The Journal of clinical investigation

2010 Volume 120, Issue 8, Page(s) 2699–2714

Abstract: Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1alpha and ... ...

Abstract	Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1alpha and HIF-2alpha, and overexpression of HIF-2alpha in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2alpha during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1alpha versus HIF-2alpha must be elucidated. We demonstrate here that mice lacking HIF-2alpha in myeloid cells (Hif2aDelta/Delta mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2alpha directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2aDelta/Delta mice displayed reduced TAM infiltration in independent murine hepatocellular and colitis-associated colon carcinoma models, and this was associated with reduced tumor cell proliferation and progression. Notably, HIF-2alpha modulated macrophage migration by regulating the expression of the cytokine receptor M-CSFR and the chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2alpha as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.
MeSH term(s)	Acute Disease ; Animals ; Basic Helix-Loop-Helix Transcription Factors/physiology ; Cell Movement ; Cytokines/genetics ; Disease Models, Animal ; Endotoxemia/immunology ; Female ; Immunity, Innate ; Inflammation/immunology ; Lipopolysaccharides/toxicity ; Macrophages/physiology ; Mice ; Mice, Inbred C57BL ; Neoplasms/immunology ; Nitric Oxide/biosynthesis ; Receptors, CXCR4/physiology
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; CXCR4 protein, mouse ; Cytokines ; Lipopolysaccharides ; Receptors, CXCR4 ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2010-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI39506
Database	MEDical Literature Analysis and Retrieval System OnLINE

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