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  1. Article ; Online: Engineering a soluble parathyroid hormone GPCR mimetic.

    Audu, Christopher O / Plati, Jessica J / Pellegrini, Maria / Mierke, Dale F

    Proteins

    2014  Volume 82, Issue 7, Page(s) 1370–1375

    Abstract: We designed and characterized a soluble mimic of the parathyroid hormone (PTH) receptor (PTH1R) that incorporates the N-terminus and third extracellular loop of PTH1R, important for ligand binding. The engineered receptor (PTH1R-NE3) was conceived to ... ...

    Abstract We designed and characterized a soluble mimic of the parathyroid hormone (PTH) receptor (PTH1R) that incorporates the N-terminus and third extracellular loop of PTH1R, important for ligand binding. The engineered receptor (PTH1R-NE3) was conceived to enable easy production and the use of standard biochemical and biophysical assays for the screening of competitive antagonists of PTH. We show that PTH1R-NE3 is folded, thermodynamically stable and selectively binds PTH. We also demonstrate the utility of our mimic by identifying a small molecule that competes with PTH in our PTH1R-NE3-based fluorescence polarization assay. Antagonists to PTH1R, a transmembrane protein belonging to the class B G-protein coupled receptor family, may provide new therapeutic options for calcium metabolism diseases like humoral hypercalcemia of malignancy.
    MeSH term(s) Humans ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Protein Engineering/methods ; Receptor, Parathyroid Hormone, Type 1/chemistry ; Receptor, Parathyroid Hormone, Type 1/genetics ; Receptor, Parathyroid Hormone, Type 1/metabolism ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Solubility
    Chemical Substances Receptor, Parathyroid Hormone, Type 1 ; Recombinant Fusion Proteins
    Language English
    Publishing date 2014-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 806683-8
    ISSN 1097-0134 ; 0887-3585
    ISSN (online) 1097-0134
    ISSN 0887-3585
    DOI 10.1002/prot.24503
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2291: Show issues Location:
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  2. Article ; Online: Harnessing the tumor suppressor function of FOXO as an alternative therapeutic approach in cancer.

    Singh, Amrik / Plati, Jessica / Khosravi-Far, Roya

    Current drug targets

    2011  Volume 12, Issue 9, Page(s) 1311–1321

    Abstract: The promotion of cellular survival, dedifferentiation, and uncontrolled proliferation via the suppression of apoptotic effectors is a fundamental characteristic of tumor cells. As substrates that are negatively regulated by oncogenic signaling cascades ... ...

    Abstract The promotion of cellular survival, dedifferentiation, and uncontrolled proliferation via the suppression of apoptotic effectors is a fundamental characteristic of tumor cells. As substrates that are negatively regulated by oncogenic signaling cascades driven by AKT, SGK (serum- and glucocorticoid-inducible kinase), IkB kinase (IKK), ERK, and cyclin-dependent kinases (CDK), forkhead box-class O (FOXO) transcription factors have emerged as bona fide tumor suppressors. These transcription factors indeed regulate a variety of cellular responses and themselves are regulated by reversible phosphorylation, acetylation, ubiquitination and miRNAs. This review will discuss our current understanding of mechanisms for FOXO regulation and the potential implications for therapeutically restoring FOXO transcriptional activity.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Cell Dedifferentiation ; Cell Proliferation ; Cell Survival ; Forkhead Transcription Factors/metabolism ; Humans ; MicroRNAs/metabolism ; Neoplasms/drug therapy ; Neoplasms/pathology ; Protein Processing, Post-Translational
    Chemical Substances Antineoplastic Agents ; Forkhead Transcription Factors ; MicroRNAs
    Language English
    Publishing date 2011-03-24
    Publishing country United Arab Emirates
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2064859-5
    ISSN 1873-5592 ; 1389-4501
    ISSN (online) 1873-5592
    ISSN 1389-4501
    DOI 10.2174/138945011796150271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5578: Show issues Location:
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  3. Article ; Online: Apoptotic cell signaling in cancer progression and therapy.

    Plati, Jessica / Bucur, Octavian / Khosravi-Far, Roya

    Integrative biology : quantitative biosciences from nano to macro

    2011  Volume 3, Issue 4, Page(s) 279–296

    Abstract: Apoptosis is a tightly regulated cell suicide program that plays an essential role in the development and maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Impairment of this native defense mechanism promotes aberrant ... ...

    Abstract Apoptosis is a tightly regulated cell suicide program that plays an essential role in the development and maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Impairment of this native defense mechanism promotes aberrant cellular proliferation and the accumulation of genetic defects, ultimately resulting in tumorigenesis, and frequently confers drug resistance to cancer cells. The regulation of apoptosis at several levels is essential to maintain the delicate balance between cellular survival and death signaling that is required to prevent disease. Complex networks of signaling pathways act to promote or inhibit apoptosis in response to various cues. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Various upstream signaling pathways can modulate apoptosis by converging on, and thereby altering the activity of, common central control points within the apoptotic signaling pathways, which involve the BCL-2 family proteins, inhibitor of apoptosis (IAP) proteins, and FLICE-inhibitory protein (c-FLIP). This review highlights the role of these fundamental regulators of apoptosis in the context of both normal apoptotic signaling mechanisms and dysregulated apoptotic pathways that can render cancer cells resistant to cell death. In addition, therapeutic strategies aimed at modulating the activity of BCL-2 family proteins, IAPs, and c-FLIP for the targeted induction of apoptosis are briefly discussed.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Disease Progression ; Humans ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; Signal Transduction/physiology
    Language English
    Publishing date 2011-02-22
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2480063-6
    ISSN 1757-9708 ; 1757-9694
    ISSN (online) 1757-9708
    ISSN 1757-9694
    DOI 10.1039/c0ib00144a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Apoptotic cell signaling in cancer progression and therapy

    Plati, Jessica / Bucur, Octavian / Khosravi-Far, Roya

    Integrative biology. 2011 Apr. 1, v. 3, no. 4

    2011  

    Abstract: Apoptosis is a tightly regulated cell suicide program that plays an essential role in the development and maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Impairment of this native defense mechanism promotes aberrant ... ...

    Abstract Apoptosis is a tightly regulated cell suicide program that plays an essential role in the development and maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Impairment of this native defense mechanism promotes aberrant cellular proliferation and the accumulation of genetic defects, ultimately resulting in tumorigenesis, and frequently confers drug resistance to cancer cells. The regulation of apoptosis at several levels is essential to maintain the delicate balance between cellular survival and death signaling that is required to prevent disease. Complex networks of signaling pathways act to promote or inhibit apoptosis in response to various cues. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Various upstream signaling pathways can modulate apoptosis by converging on, and thereby altering the activity of, common central control points within the apoptotic signaling pathways, which involve the BCL-2 family proteins, inhibitor of apoptosis (IAP) proteins, and FLICE-inhibitory protein (c-FLIP). This review highlights the role of these fundamental regulators of apoptosis in the context of both normal apoptotic signaling mechanisms and dysregulated apoptotic pathways that can render cancer cells resistant to cell death. In addition, therapeutic strategies aimed at modulating the activity of BCL-2 family proteins, IAPs, and c-FLIP for the targeted induction of apoptosis are briefly discussed.
    Keywords apoptosis ; carcinogenesis ; cell proliferation ; death domain receptors ; drug resistance ; genetic disorders ; homeostasis ; ligands ; mutagens ; neoplasm cells ; neoplasm progression ; neoplasms ; signal transduction ; therapeutics
    Language English
    Dates of publication 2011-0401
    Size p. 279-296.
    Publishing place The Royal Society of Chemistry
    Document type Article
    ZDB-ID 2480063-6
    ISSN 1757-9708 ; 1757-9694
    ISSN (online) 1757-9708
    ISSN 1757-9694
    DOI 10.1039/c0ib00144a
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities.

    Plati, Jessica / Bucur, Octavian / Khosravi-Far, Roya

    Journal of cellular biochemistry

    2008  Volume 104, Issue 4, Page(s) 1124–1149

    Abstract: Apoptosis is a tightly regulated cell suicide program that plays an essential role in the maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Defects in this native defense mechanism promote malignant transformation and ... ...

    Abstract Apoptosis is a tightly regulated cell suicide program that plays an essential role in the maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Defects in this native defense mechanism promote malignant transformation and frequently confer chemoresistance to transformed cells. Indeed, the evasion of apoptosis has been recognized as a hallmark of cancer. Given that multiple mechanisms function at many levels to orchestrate the regulation of apoptosis, a multitude of opportunities for apoptotic dysregulation are present within the intricate signaling network of cell. Several of the molecular mechanisms by which cancer cells are protected from apoptosis have been elucidated. These advances have facilitated the development of novel apoptosis-inducing agents that have demonstrated single-agent activity against various types of cancers cells and/or sensitized resistant cancer cells to conventional cytotoxic therapies. Herein, we will highlight several of the central modes of apoptotic dysregulation found in cancer. We will also discuss several therapeutic strategies that aim to reestablish the apoptotic response, and thereby eradicate cancer cells, including those that demonstrate resistance to traditional therapies.
    MeSH term(s) Animals ; Apoptosis ; Apoptosis Regulatory Proteins/physiology ; Humans ; Neoplasms/drug therapy ; Neoplasms/pathology ; Signal Transduction
    Chemical Substances Apoptosis Regulatory Proteins
    Language English
    Publishing date 2008-05-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.21707
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1114: Show issues Location:
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  6. Article: Structural features of parathyroid hormone receptor coupled to Galpha(s)-protein.

    Plati, Jessica / Tsomaia, Natia / Piserchio, Andrea / Mierke, Dale F

    Biophysical journal

    2006  Volume 92, Issue 2, Page(s) 535–540

    Abstract: The molecular basis of the activation of G-proteins by the G-protein coupled receptor for parathyroid hormone (PTH) is unknown. Employing a combination of NMR methods and computer-based structural refinement, structural features involved in the ... ...

    Abstract The molecular basis of the activation of G-proteins by the G-protein coupled receptor for parathyroid hormone (PTH) is unknown. Employing a combination of NMR methods and computer-based structural refinement, structural features involved in the activation of Galpha(s) by the PTH receptor (PTH1R) have been determined. Focusing on the C-terminus of the third intracellular loop (IC3), previously shown to be important for Galpha(s) activation by PTH1R, the structure of this region, PTH1R(402-408), while bound to Galpha(s), was determined by transferred nuclear Overhauser effect spectroscopy. The relative topological orientation of the IC3 while associated with Galpha(s) was determined by saturation transfer difference spectroscopy. These experimental data were incorporated into molecular dynamics simulations of the PTH1R and Galpha(s) to provide atomic insight into the receptor-protein interactions important for PTH signaling and a structural framework to analyze previous mutagenesis studies of Galpha(s). These data provide the first step toward development of a molecular mechanism for the signaling profile of PTH1R, an important regulator of calcium levels in the bloodstream.
    MeSH term(s) Binding Sites ; Computer Simulation ; GTP-Binding Protein alpha Subunits/chemistry ; GTP-Binding Protein alpha Subunits/ultrastructure ; Models, Chemical ; Models, Molecular ; Molecular Conformation ; Protein Binding ; Receptor, Parathyroid Hormone, Type 1/chemistry ; Receptor, Parathyroid Hormone, Type 1/ultrastructure ; Structure-Activity Relationship
    Chemical Substances GTP-Binding Protein alpha Subunits ; Receptor, Parathyroid Hormone, Type 1
    Language English
    Publishing date 2006-10-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1529/biophysj.106.094813
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 235: Show issues Location:
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    Zs.MO 2: Show issues

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  7. Article ; Online: Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier.

    Bhasin, Manoj K / Ndebele, Kenneth / Bucur, Octavian / Yee, Eric U / Otu, Hasan H / Plati, Jessica / Bullock, Andrea / Gu, Xuesong / Castan, Eduardo / Zhang, Peng / Najarian, Robert / Muraru, Maria S / Miksad, Rebecca / Khosravi-Far, Roya / Libermann, Towia A

    Oncotarget

    2016  Volume 7, Issue 17, Page(s) 23263–23281

    Abstract: Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification.: Experimental design: Optimized meta-analysis of PDAC ... ...

    Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification.
    Experimental design: Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5-gene biomarker panel was measured by qRT-PCR in microdissected patient-derived FFPE tissues. Cell-based assays assessed impact of two of these biomarkers, TMPRSS4 and ECT2, on PDAC cells.
    Results: A 5-gene PDAC classifier (TMPRSS4, AHNAK2, POSTN, ECT2, SERPINB5) achieved on average 95% sensitivity and 89% specificity in discriminating PDAC from non-tumor samples in four training sets and similar performance (sensitivity = 94%, specificity = 89.6%) in five independent validation datasets. This classifier accurately discriminated PDAC from chronic pancreatitis (AUC = 0.83), other cancers (AUC = 0.89), and non-tumor from PDAC precursors (AUC = 0.92) in three independent datasets. Importantly, the classifier distinguished PanIN from healthy pancreas in the PDX1-Cre;LSL-KrasG12D PDAC mouse model. Discriminatory expression of the PDAC classifier genes was confirmed in microdissected FFPE samples of PDAC and matched surrounding non-tumor pancreas or pancreatitis. Notably, knock-down of TMPRSS4 and ECT2 reduced PDAC soft agar growth and cell viability and TMPRSS4 knockdown also blocked PDAC migration and invasion.
    Conclusions: This study identified and validated a highly accurate 5-gene PDAC classifier for discriminating PDAC and early precursor lesions from non-malignant tissue that may facilitate early diagnosis and risk stratification upon validation in prospective clinical trials. Cell-based experiments of two overexpressed proteins encoded by the panel, TMPRSS4 and ECT2, suggest a causal link to PDAC development and progression, confirming them as potential therapeutic targets.
    MeSH term(s) Adenocarcinoma/classification ; Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Biomarkers, Tumor/genetics ; Carcinoma in Situ/classification ; Carcinoma in Situ/genetics ; Carcinoma in Situ/pathology ; Carcinoma, Pancreatic Ductal/classification ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/pathology ; Case-Control Studies ; Disease Progression ; Early Detection of Cancer ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Humans ; Membrane Proteins/genetics ; Pancreatic Neoplasms/classification ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Prognosis ; Proto-Oncogene Proteins/genetics ; Serine Endopeptidases/genetics ; Transcriptome ; Pancreatic Neoplasms
    Chemical Substances Biomarkers, Tumor ; ECT2 protein, human ; Membrane Proteins ; Proto-Oncogene Proteins ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS4 protein, human (EC 3.4.21.-)
    Language English
    Publishing date 2016-02-12
    Publishing country United States
    Document type Journal Article ; Meta-Analysis
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.8139
    Database MEDical Literature Analysis and Retrieval System OnLINE

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