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Article ; Online: An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.

Xylinas, Evanguelos / Hassler, Melanie R / Zhuang, Dazhong / Krzywinski, Martin / Erdem, Zeynep / Robinson, Brian D / Elemento, Olivier / Clozel, Thomas / Shariat, Shahrokh F

Biomolecules

2016 Volume 6, Issue 3

Abstract: Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) ... ...

Abstract	Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and no biomarker currently exists to identify these patients. It is also not clear whether a strategy to sensitize chemoresistant patients may exist. We sought to identify cisplatin-resistance patterns in preclinical models of bladder cancer, and test whether treatment with the epigenetic modifier decitabine is able to sensitize cisplatin-resistant bladder cancer cell lines. Using a screening approach in cisplatin-resistant bladder cancer cell lines, we identified dysregulated genes by RNA sequencing (RNAseq) and DNA methylation assays. DNA methylation analysis of tumors from 18 patients receiving cisplatin-based chemotherapy was used to confirm in vitro results. Cisplatin-resistant bladder cancer cells were treated with decitabine to investigate epigenetic sensitization of resistant cell lines. Our results show that HOXA9 promoter methylation status is associated with response to cisplatin-based chemotherapy in bladder cancer cell lines and in metastatic bladder cancer. Bladder cancer cells resistant to cisplatin chemotherapy can be sensitized to cisplatin by the DNA methylation inhibitor decitabine. Our data suggest that HOXA9 promoter methylation could serve as potential predictive biomarker and decitabine might sensitize resistant tumors in patients receiving cisplatin-based chemotherapy.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Cisplatin/pharmacology ; Doxorubicin/pharmacology ; Drug Resistance, Neoplasm/genetics ; Epigenomics ; Etoposide/pharmacology ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Hydroxamic Acids/pharmacology ; Methylation ; Neoadjuvant Therapy ; Promoter Regions, Genetic ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/metabolism ; Vinblastine/pharmacology
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Homeodomain Proteins ; Hydroxamic Acids ; homeobox protein HOXA9 ; vorinostat (58IFB293JI) ; Vinblastine (5V9KLZ54CY) ; Etoposide (6PLQ3CP4P3) ; decitabine (776B62CQ27) ; Doxorubicin (80168379AG) ; Azacitidine (M801H13NRU) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2016-09-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom6030037
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Article: Increased CCAAT enhancer-binding protein epsilon (C/EBPepsilon) expression and premature apoptosis in myeloid cells expressing Gfi-1 N382S mutant associated with severe congenital neutropenia.

Zhuang, Dazhong / Qiu, Yaling / Kogan, Scott C / Dong, Fan

The Journal of biological chemistry

2006 Volume 281, Issue 16, Page(s) 10745–10751

Abstract: Granulocyte-colony-stimulating factor (G-CSF) stimulates the activation of multiple signaling pathways, leading to alterations in the activities of transcription factors. Gfi-1 is a zinc finger transcriptional repressor that is required for ... ...

Abstract	Granulocyte-colony-stimulating factor (G-CSF) stimulates the activation of multiple signaling pathways, leading to alterations in the activities of transcription factors. Gfi-1 is a zinc finger transcriptional repressor that is required for granulopoiesis. How Gfi-1 acts in myeloid cells is poorly understood. We show here that the expression of Gfi-1 was up-regulated during G-CSF-induced granulocytic differentiation in myeloid 32D cells. Truncation of the carboxyl terminus of the G-CSF receptor, as seen in patients with acute myeloid leukemia evolving from severe congenital neutropenia, disrupted Gfi-1 up-regulation by G-CSF. Ectopic expression of a dominant negative Gfi-1 mutant, N382S, which was associated with severe congenital neutropenia, resulted in premature apoptosis and reduced proliferation of cells induced to differentiate with G-CSF. The expression of neutrophil elastase (NE) and CCAAT enhancer-binding protein epsilon (C/EBPepsilon) was significantly increased in 32D cells expressing N382S. In contrast, overexpression of wild type Gfi-1 abolished G-CSF-induced up-regulation of C/EBPepsilon but had no apparent effect on NE up-regulation by G-CSF. Notably, G-CSF-dependent proliferation and survival were inhibited upon overexpression of C/EBPepsilon but not NE. These data indicate that Gfi-1 down-regulates C/EBPepsilon expression and suggest that increased expression of C/EBPepsilon as a consequence of loss of Gfi-1 function may be deleterious to the proliferation and survival of early myeloid cells.
MeSH term(s)	Animals ; Apoptosis ; Blotting, Western ; CCAAT-Enhancer-Binding Proteins/biosynthesis ; Cell Cycle ; Cell Differentiation ; Cell Line ; Cell Proliferation ; Cell Survival ; DNA/metabolism ; DNA Fragmentation ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Gene Expression Regulation ; Genetic Vectors ; Granulocyte Colony-Stimulating Factor/metabolism ; Granulocytes/metabolism ; Interleukin-3/metabolism ; Mice ; Mutation ; Myeloid Cells/metabolism ; Neutropenia/congenital ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA, Messenger/metabolism ; Signal Transduction ; Time Factors ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription Factors/physiology ; Transcription, Genetic ; Transfection ; Up-Regulation ; Zinc Fingers
Chemical Substances	CCAAT-Enhancer-Binding Proteins ; Cebpe protein, mouse ; DNA-Binding Proteins ; Gfi1 protein, mouse ; Interleukin-3 ; Proto-Oncogene Proteins c-bcl-2 ; RNA, Messenger ; Transcription Factors ; Granulocyte Colony-Stimulating Factor (143011-72-7) ; DNA (9007-49-2)
Language	English
Publishing date	2006-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M510924200
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Article: Tyrosine 729 of the G-CSF receptor controls the duration of receptor signaling: involvement of SOCS3 and SOCS1.

Zhuang, Dazhong / Qiu, Yaling / Haque, S Jaharul / Dong, Fan

Journal of leukocyte biology

2005 Volume 78, Issue 4, Page(s) 1008–1015

Abstract: Mutations in the granulocyte-colony stimulating factor receptor (G-CSF-R) gene resulting in carboxy terminal truncation have been associated with acute myeloid leukemia (AML). The truncated G-CSF-R from AML patients mediate enhanced and prolonged ... ...

Abstract	Mutations in the granulocyte-colony stimulating factor receptor (G-CSF-R) gene resulting in carboxy terminal truncation have been associated with acute myeloid leukemia (AML). The truncated G-CSF-R from AML patients mediate enhanced and prolonged activation of signal transducer and activator of transcription 5 (Stat5). It has been shown that Src homology-2 (SH2)-containing tyrosine phosphatase-1 attenuates the intensity of G-CSF-induced Stat5 activation through interacting with the carboxy terminus of the G-CSF-R. Using a series of tyrosine-to-phenylalanine substitution mutants, we show here that tyrosine (Tyr) 729, located in the carboxy terminus of the G-CSF-R, controls the duration of G-CSF-stimulated activation of Stat5, Akt, and extracellular signal-regulated kinase 1/2. It is interesting that activation of these signaling molecules by G-CSF was prolonged by pretreating cells with actinomycin D or cyclohexamide, suggesting that de novo protein synthesis is required for appropriate termination of G-CSF-R signaling. The transcripts for suppressor of cytokine signaling 3 (SOCS3) and SOCS1 were up-regulated rapidly upon G-CSF stimulation. Expression of SOCS3 or SOCS1, but not SOCS2 and cytokine-inducible SH2 domain-containing protein, completely suppressed G-CSF-induced Stat5 activation but had only a weak effect on Stat5 activation mediated by the receptor mutant lacking Tyr 729. SOCS1 and SOCS3 also inhibited G-CSF-dependent cell proliferation, but the inhibitory effect of the two SOCS proteins on cell proliferation was diminished when Tyr 729 of the G-CSF-R was mutated. These data indicate that Tyr 729 of the G-CSF-R is required for SOCS1- and SOCS3-mediated negative regulation of G-CSF-R signaling and that the duration and intensity of G-CSF-induced Stat5 activation are regulated by two distinct mechanisms.
MeSH term(s)	Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Humans ; Mice ; Mutation ; Receptors, Granulocyte Colony-Stimulating Factor/genetics ; Receptors, Granulocyte Colony-Stimulating Factor/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins/genetics ; Suppressor of Cytokine Signaling Proteins/metabolism ; Tyrosine/genetics ; Tyrosine/metabolism
Chemical Substances	Carrier Proteins ; Receptors, Granulocyte Colony-Stimulating Factor ; Repressor Proteins ; Socs1 protein, mouse ; Socs3 protein, mouse ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; Tyrosine (42HK56048U)
Language	English
Publishing date	2005-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1189/jlb.0105032
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Article: The G-CSF receptor carboxyl terminus, truncated in AML/SCN, is required for induction of a Stat5 protease activity.

Qiu, Yaling / Zhuang, Dazhong / MacRae, Alexandra / Dong, Fan

Leukemia research

2005 Volume 29, Issue 10, Page(s) 1153–1162

Abstract: Granulocyte colony-stimulating factor (G-CSF) has been shown to stimulate the activation of the signal transducer and activator of transcription 5 (Stat5). We show here that G-CSF-stimulated activation of Stat5 was attenuated when myeloid cells were ... ...

Abstract	Granulocyte colony-stimulating factor (G-CSF) has been shown to stimulate the activation of the signal transducer and activator of transcription 5 (Stat5). We show here that G-CSF-stimulated activation of Stat5 was attenuated when myeloid cells were induced to differentiate with G-CSF. Attenuated activation of Stat5 correlated with reduced Stat5 protein levels, which was associated with upregulation of a Stat5 protease activity. Carboxyl terminal truncation of the G-CSF receptor or expression of leukemogenic proteins Bcr-Abl and Tel-Jak2 abolished the upregulation of the Stat5 protease activity by G-CSF. These data add to our understanding of the roles of G-CSF and Stat5 in normal granulopoiesis and leukemogenesis.
MeSH term(s)	Animals ; Cell Differentiation ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Enzyme Activation ; Fusion Proteins, bcr-abl ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mice ; Milk Proteins/genetics ; Milk Proteins/metabolism ; Myeloid Cells/cytology ; Myeloid Cells/metabolism ; Neutropenia/congenital ; Neutropenia/genetics ; Neutropenia/metabolism ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Receptors, Granulocyte Colony-Stimulating Factor/genetics ; Receptors, Granulocyte Colony-Stimulating Factor/metabolism ; STAT5 Transcription Factor ; Sequence Deletion ; Signal Transduction ; Trans-Activators/genetics ; Trans-Activators/metabolism
Chemical Substances	DNA-Binding Proteins ; Milk Proteins ; Oncogene Proteins, Fusion ; Receptors, Granulocyte Colony-Stimulating Factor ; STAT5 Transcription Factor ; TEL-JAK2 fusion protein, human ; Trans-Activators ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Fusion Proteins, bcr-abl (EC 2.7.10.2)
Language	English
Publishing date	2005-04-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	752396-8
ISSN	1873-5835 ; 0145-2126
ISSN (online)	1873-5835
ISSN	0145-2126
DOI	10.1016/j.leukres.2005.03.005
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Article: Increased CCAAT Enhancer-binding Protein [epsilon] (C/EBP[epsilon]) Expression and Premature Apoptosis in Myeloid Cells Expressing Gfi-1 N382S Mutant Associated with Severe Congenital Neutropenia

Zhuang, Dazhong / Qiu, Yaling / Kogan, Scott C / Dong, Fan

Journal of biological chemistry. 2006 Apr. 21, v. 281, no. 16

2006

Abstract	Granulocyte-colony-stimulating factor (G-CSF) stimulates the activation of multiple signaling pathways, leading to alterations in the activities of transcription factors. Gfi-1 is a zinc finger transcriptional repressor that is required for granulopoiesis. How Gfi-1 acts in myeloid cells is poorly understood. We show here that the expression of Gfi-1 was up-regulated during G-CSF-induced granulocytic differentiation in myeloid 32D cells. Truncation of the carboxyl terminus of the G-CSF receptor, as seen in patients with acute myeloid leukemia evolving from severe congenital neutropenia, disrupted Gfi-1 up-regulation by G-CSF. Ectopic expression of a dominant negative Gfi-1 mutant, N382S, which was associated with severe congenital neutropenia, resulted in premature apoptosis and reduced proliferation of cells induced to differentiate with G-CSF. The expression of neutrophil elastase (NE) and CCAAT enhancer-binding protein [epsilon] (C/EBP[epsilon]) was significantly increased in 32D cells expressing N382S. In contrast, overexpression of wild type Gfi-1 abolished G-CSF-induced up-regulation of C/EBP[epsilon] but had no apparent effect on NE up-regulation by G-CSF. Notably, G-CSF-dependent proliferation and survival were inhibited upon overexpression of C/EBP[epsilon] but not NE. These data indicate that Gfi-1 down-regulates C/EBP[epsilon] expression and suggest that increased expression of C/EBP[epsilon] as a consequence of loss of Gfi-1 function may be deleterious to the proliferation and survival of early myeloid cells.
Language	English
Dates of publication	2006-0421
Size	p. 10745-10751.
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 ; Online: Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinib.

de Martino, Michela / Zhuang, Dazhong / Klatte, Tobias / Rieken, Malte / Rouprêt, Morgan / Xylinas, Evanguelos / Clozel, Thomas / Krzywinski, Martin / Elemento, Olivier / Shariat, Shahrokh F

Cancer biology & therapy

2014 Volume 15, Issue 9, Page(s) 1239–1247

Abstract: Lapatinib, a dual tyrosine kinase inhibitor of ErbB1 and ErbB2, shows a clinical benefit in a subset of patients with advanced urothelial bladder cancer (UBC). We hypothesized that the corresponding gene, ERBB2, is affected by mutations in a subset of ... ...

Abstract	Lapatinib, a dual tyrosine kinase inhibitor of ErbB1 and ErbB2, shows a clinical benefit in a subset of patients with advanced urothelial bladder cancer (UBC). We hypothesized that the corresponding gene, ERBB2, is affected by mutations in a subset of UBC and that these mutations impact ErbB2 function, signaling, UBC proliferation, gene expression, and predict response to lapatinib. We found ERBB2 mutations in 5 of 33 UBC cell lines (15%), all of which were derived from invasive or high grade tumors. Phosphorylation and activation of ErbB2 and its downstream pathways were markedly enhanced in mutated cell lines compared with the ERBB2 wild-type. In addition, the gene expression profile was distinct, specifically for genes encoding for proteins of the extracellular matrix. RT112 cells infected with ERBB2 mutants showed a particular growth pattern ("mini-foci"). Upon treatment with lapatinib, 93% of these "mini-foci" were reversed. The sensitivity to lapatinib was greatest among cell lines with ERBB2 mutations. In conclusion, ERBB2 mutations occur in a subset of UBC and impact proliferation, signaling, gene expression and predict a greater response to lapatinib. If confirmed in the clinical setting, this may lead the way toward personalized treatment of a subset of UBC.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Humans ; In Vitro Techniques ; Inhibitory Concentration 50 ; Lapatinib ; Mutation ; Quinazolines/pharmacology ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism ; Urinary Bladder Neoplasms/metabolism ; Urinary Bladder Neoplasms/pathology
Chemical Substances	Antineoplastic Agents ; Quinazolines ; Lapatinib (0VUA21238F) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2014-07-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2146305-0
ISSN	1555-8576 ; 1538-4047
ISSN (online)	1555-8576
ISSN	1538-4047
DOI	10.4161/cbt.29687
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Zs.A 5887: Show issues

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Article: YWK-II protein/APLP2 in mouse gametes: potential role in fertilization.

Zhuang, Dazhong / Qiao, Yuan / Zhang, Xiaodong / Miao, Shiying / Koide, S S / Wang, Linfang

Molecular reproduction and development

2006 Volume 73, Issue 1, Page(s) 61–67

Abstract: YWK-II protein is a sperm membrane component, structurally related to human placenta amyloid precursor protein homolog (APPH) and rat amyloid precursor-like protein 2 (APLP2). Its transmembrane-cytoplasmic domain has high homology (70.6%) with that of ... ...

Abstract	YWK-II protein is a sperm membrane component, structurally related to human placenta amyloid precursor protein homolog (APPH) and rat amyloid precursor-like protein 2 (APLP2). Its transmembrane-cytoplasmic domain has high homology (70.6%) with that of betaA4-amyloid precursor protein (APP) found in brain plaques of subjects with Alzheimer's disease. The gene encoding the YWK-II protein is expressed in various mammalian cells and tissues. In the present study, splicing patterns of YWK-II mRNA and the content of YWK-II mRNA in mouse testes, eggs, and cumulus cells were determined. Three different YWK-II transcripts were found in testes and eggs, while cumulus cells contained an additional transcript. In mouse eggs, the content of YWK-II transcript exceeded that of APP. An alternative splicing region was located in the vicinity of the kunitz protease inhibitor (KPI) domain, which may be the basis for the formation of multiple transcripts. YWK-II protein was immunolocated in male and female gametes. It was localized in the plasma membrane of mouse eggs and spermatozoa. In the male reproductive system of the mouse, the YWK-II gene was expressed in germ cells at various stages of differentiation. In mature spermatozoa, the YWK-II protein occurred in the plasma membrane enveloping the acrosome. Triggering the acrosome reaction incited a release of the YWK-II protein attached to the liberated membrane vesicles. The occurrence of the YWK-II protein in the plasma membranes of mouse gametes suggests its involvement in sperm-egg interaction.
MeSH term(s)	Alternative Splicing/genetics ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/physiology ; Animals ; Female ; Fertilization/physiology ; Male ; Mice ; Microscopy, Immunoelectron ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/physiology ; Ovum/physiology ; Protein Structure, Tertiary/genetics ; Spermatozoa/physiology ; Testis/physiology
Chemical Substances	APLP2 protein, human ; Amyloid beta-Protein Precursor ; Nerve Tissue Proteins
Language	English
Publishing date	2006-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	20321-x
ISSN	1098-2795 ; 1040-452X
ISSN (online)	1098-2795
ISSN	1040-452X
DOI	10.1002/mrd.20380
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Zs.A 2759: Show issues

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Article ; Online: Krüppel-like factor 9 and progesterone receptor coregulation of decidualizing endometrial stromal cells: implications for the pathogenesis of endometriosis.

Pabona, John Mark P / Simmen, Frank A / Nikiforov, Mikhail A / Zhuang, DaZhong / Shankar, Kartik / Velarde, Michael C / Zelenko, Zara / Giudice, Linda C / Simmen, Rosalia C M

The Journal of clinical endocrinology and metabolism

2012 Volume 97, Issue 3, Page(s) E376–92

Abstract: Context: Endometriosis is characterized by progesterone resistance and associated with infertility. Krüppel-like factor 9 (KLF9) is a progesterone receptor (PGR)-interacting protein, and mice null for Klf9 are subfertile. Whether loss of KLF9 expression ...

Abstract	Context: Endometriosis is characterized by progesterone resistance and associated with infertility. Krüppel-like factor 9 (KLF9) is a progesterone receptor (PGR)-interacting protein, and mice null for Klf9 are subfertile. Whether loss of KLF9 expression contributes to progesterone resistance of eutopic endometrium of women with endometriosis is unknown. Objective: The aims were to investigate 1) KLF9 expression in eutopic endometrium of women with and without endometriosis, 2) effects of attenuated KLF9 expression on WNT-signaling component expression and on WNT inhibitor Dickkopf-1 promoter activity in human endometrial stromal cells (HESC), and 3) PGR and KLF9 coregulation of the stromal transcriptome network. Methods: Transcript levels of KLF9, PGR, and WNT signaling components were measured in eutopic endometrium of women with and without endometriosis. Transcript and protein levels of WNT signaling components in HESC transfected with KLF9 and/or PGR small interfering RNA were analyzed by quantitative RT-PCR and Western blot. KLF9 and PGR coregulation of Dickkopf-1 promoter activity was evaluated using human Dickkopf-1-luciferase promoter/reporter constructs and by chromatin immunoprecipitation. KLF9 and PGR signaling networks were analyzed by gene expression array profiling. Results: Eutopic endometrium from women with endometriosis had reduced expression of KLF9 mRNA together with those of PGR-B, WNT4, WNT2, and DKK1. KLF9 and PGR were recruited to the DKK1 promoter and modified each other's transactivity. In HESC, KLF9 and PGR coregulated components of the WNT, cytokine, and IGF gene networks that are implicated in endometriosis and infertility. Conclusion: Loss of KLF9 coregulation of endometrial stromal PGR-responsive gene networks may underlie progesterone resistance in endometriosis.
MeSH term(s)	Adult ; Endometriosis/etiology ; Endometriosis/genetics ; Endometriosis/metabolism ; Endometriosis/pathology ; Endometrium/metabolism ; Endometrium/pathology ; Female ; Gene Expression ; Humans ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Promoter Regions, Genetic ; Receptors, Progesterone/genetics ; Receptors, Progesterone/metabolism ; Signal Transduction/physiology ; Stromal Cells/metabolism ; Stromal Cells/pathology ; Wnt Signaling Pathway/physiology
Chemical Substances	KLF9 protein, human ; Kruppel-Like Transcription Factors ; Receptors, Progesterone
Language	English
Publishing date	2012-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/jc.2011-2562
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Article ; Online: KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells.

Mannava, Sudha / Zhuang, DaZhong / Nair, Jayakumar R / Bansal, Rajat / Wawrzyniak, Joseph A / Zucker, Shoshanna N / Fink, Emily E / Moparthy, Kalyana C / Hu, Qiang / Liu, Song / Boise, Lawrence H / Lee, Kelvin P / Nikiforov, Mikhail A

Blood

2011 Volume 119, Issue 6, Page(s) 1450–1458

Abstract: Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators ... ...

Abstract	Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators required for bortezomib-induced apoptosis in MM cells are largely unknown. Using gene expression profiling, we identified 36 transcription factors that displayed altered expression in MM cells treated with bortezomib. Analysis of a publically available database identified Kruppel-like family factor 9 (KLF9) as the only transcription factor with significantly higher basal expression in MM cells from patients who responded to bortezomib compared with nonresponders. We demonstrated that KLF9 in cultured MM cells was up-regulated by bortezomib; however, it was not through the induction of endoplasmic reticulum stress. Instead, KLF9 levels correlated with bortezomib-dependent inhibition of histone deacetylases (HDAC) and were increased by the HDAC inhibitor LBH589 (panobinostat). Furthermore, bortezomib induced binding of endogenous KLF9 to the promoter of the proapoptotic gene NOXA. Importantly, KLF9 knockdown impaired NOXA up-regulation and apoptosis caused by bortezomib, LBH589, or a combination of theses drugs, whereas KLF9 overexpression induced apoptosis that was partially NOXA-dependent. Our data identify KLF9 as a novel and potentially clinically relevant transcriptional regulator of drug-induced apoptosis in MM cells.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Boronic Acids/pharmacology ; Bortezomib ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hydroxamic Acids/pharmacology ; Indoles ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Multiple Myeloma/genetics ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Oligonucleotide Array Sequence Analysis ; Panobinostat ; Promoter Regions, Genetic/genetics ; Protein Binding ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrazines/pharmacology ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Antineoplastic Agents ; Boronic Acids ; Hydroxamic Acids ; Indoles ; KLF9 protein, human ; Kruppel-Like Transcription Factors ; PMAIP1 protein, human ; Proto-Oncogene Proteins c-bcl-2 ; Pyrazines ; Transcription Factors ; Bortezomib (69G8BD63PP) ; Panobinostat (9647FM7Y3Z)
Language	English
Publishing date	2011-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2011-04-346676
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Article: Delineation of the functional domains of the extracellular region of YWK-II Protein/APLP2 of sperm membrane.

Zhuang, Dazhong / Wang, Yong / Yang, Chunbo / Qiao, Yuan / Miao, Shiying / Koide, Samuel S / Wang, Linfang

Frontiers in bioscience : a journal and virtual library

2006 Volume 11, Page(s) 2371–2380

Abstract: The sperm membrane protein, designated as YWK-II protein/APLP2, is a member of the amyloid precursor protein (APP) superfamily and is a type I transmembrane protein involved in fertilization. Here, the structure-function of the domains of YWK-II protein ... ...

Abstract	The sperm membrane protein, designated as YWK-II protein/APLP2, is a member of the amyloid precursor protein (APP) superfamily and is a type I transmembrane protein involved in fertilization. Here, the structure-function of the domains of YWK-II protein was examined. Five segments with overlapping ends encompassing the entire extracellular region of mouse YWK-II gene were prepared, cloned and separately expressed in E. coli. The recombinant YWK-II segments were fused with glutathione S-transferase (GST), purified and evaluated for their antifertility activities by measuring their capacity to block in vitro mouse sperm-egg interaction. The structural domain(s) involved in the fertilization process was identified. The polypeptide segment corresponding to position 22-207 of YWK-II-763 inhibited the early stage of fertilization when the spermatozoa interacted with zona-free eggs; whereas the polypeptide segment 201-395 (lacking 309-364) of YWK-II-763 blocked sperm-egg membrane fusion. The remaining three segments, 201-395, 389-574 and 517-704 (lacking 613-624) of YWK-II-763, did not influence the in vitro fertilization process. The present results suggest that segment 22-308 of YWK-II-763 participates in the binding and fusion of sperm and egg plasma membranes thereby promoting fertilization.
MeSH term(s)	Amino Acid Sequence ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/physiology ; Animals ; Cell Membrane ; Escherichia coli ; Female ; Glutathione Transferase/metabolism ; Male ; Membrane Proteins ; Mice ; Molecular Sequence Data ; Oocytes ; Protease Inhibitors ; Sperm-Ovum Interactions/physiology ; Spermatozoa/chemistry ; Spermatozoa/physiology ; Structure-Activity Relationship
Chemical Substances	Amyloid beta-Protein Precursor ; Aplp2 protein, mouse ; Membrane Proteins ; Protease Inhibitors ; Glutathione Transferase (EC 2.5.1.18)
Language	English
Publishing date	2006-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2141320-4
ISSN	1093-9946
ISSN	1093-9946
DOI	10.2741/1976
Database	MEDical Literature Analysis and Retrieval System OnLINE

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