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2.
Oncogene ; 32(17): 2179-88, 2013 Apr 25.
Article in English | MEDLINE | ID: mdl-22689062

ABSTRACT

The oncogenic MUC1 C-terminal subunit (MUC1-C) subunit is aberrantly overexpressed in most human breast cancers by mechanisms that are not well understood. The present studies demonstrate that stimulation of non-malignant MCF-10A cells with epidermal growth factor (EGF) or heregulin (HRG) results in marked upregulation of MUC1-C translation. Growth factor-induced MUC1-C translation was found to be mediated by PI3KAKT, and not by MEKERK1/2, signaling. We also show that activation of the mammalian target of rapamycin complex 1 (mTORC1)ribosomal protein S6 kinase 1 (S6K1) pathway decreases tumor suppressor programmed cell death protein 4 (PDCD4), an inhibitor of the eIF4A RNA helicase, and contributes to the induction of MUC1-C translation. In concert with these results, treatment of growth factor-stimulated MCF-10A cells with the eIF4A RNA helicase inhibitors, silvestrol and CR-1-31-B, blocked increases in MUC1-C abundance. The functional significance of the increase in MUC1-C translation is supported by the demonstration that MUC1-C, in turn, forms complexes with EGF receptor (EGFR) and promotes EGFR-mediated activation of the PI3KAKT pathway and the induction of growth. Compared with MCF-10A cells, constitutive overexpression of MUC1-C in breast cancer cells was unaffected by EGF stimulation, but was blocked by inhibiting PI3KAKT signaling. The overexpression of MUC1-C in breast cancer cells was also inhibited by blocking eIF4A RNA helicase activity with silvestrol and CR-1-31-B. These findings indicate that EGF-induced MUC1-C expression is mediated by the PI3KAKT pathway and the eIF4A RNA helicase, and that this response promotes EGFR signaling in an autoinductive loop. The findings also indicate that targeting the eIF4A RNA helicase is a novel approach for blocking MUC1-C overexpression in breast cancer cells.


Subject(s)
Eukaryotic Initiation Factor-4A/physiology , Mucin-1/biosynthesis , Protein Biosynthesis , Protein Subunits/biosynthesis , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Cell Proliferation , Down-Regulation , Epidermal Growth Factor/physiology , ErbB Receptors/metabolism , Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Gene Expression , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Mucin-1/genetics , Neuregulin-1/physiology , Phosphatidylinositol 3-Kinases/metabolism , Protein Subunits/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Triterpenes/pharmacology
3.
Oncogene ; 32(7): 861-71, 2013 Feb 14.
Article in English | MEDLINE | ID: mdl-22484424

ABSTRACT

Levels of eukaryotic initiation factor 4E (eIF4E) are frequently elevated in human cancers and in some instances have been associated with poor prognosis and outcome. Here we utilize transgenic and allograft breast cancer models to demonstrate that increased mammalian target of rapamycin (mTOR) signalling can be a significant contributor to breast cancer progression in vivo. Suppressing mTOR activity, as well as levels and activity of the downstream translation regulators, eIF4E and eIF4A, delayed breast cancer progression, onset of associated pulmonary metastasis in vivo and breast cancer cell invasion and migration in vitro. Translation of vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP9) and cyclin D1 mRNAs, which encode products associated with the metastatic phenotype, is inhibited upon eIF4E suppression. Our results indicate that the mTOR/eIF4F axis is an important contributor to tumor maintenance and progression programs in breast cancer. Targeting this pathway may be of therapeutic benefit.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma/genetics , Carcinoma/pathology , Eukaryotic Initiation Factor-4F/genetics , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Progression , Eukaryotic Initiation Factor-4F/antagonists & inhibitors , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/physiology , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mice, Transgenic , RNA Interference/drug effects , RNA Interference/physiology , RNA, Small Interfering/pharmacology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/physiology
4.
J Nat Prod ; 71(4): 581-8, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18257535

ABSTRACT

Computer-assisted structure elucidation (CASE) using a combination of 1D and 2D NMR data has been available for a number of years. These algorithms can be considered as "logic machines" capable of deriving all plausible structures from a set of structural constraints or "axioms", defined by the spectroscopic data and associated chemical information or prior knowledge. CASE programs allow the spectroscopist not only to determine structures from spectroscopic data but also to study the dependence of the proposed structure on changes to the set of axioms. In this article, we describe the application of the ACD/Structure Elucidator expert system to help resolve the conflict between two different hypothetical hexacyclinol structures derived by different researchers from the NMR spectra of this complex natural product. It has been shown that the combination of algorithms for both structure elucidation and structure validation delivered by the expert system enables the identification of the most probable structure as well as the associated chemical shift assignments.


Subject(s)
Algorithms , Epoxy Compounds/chemistry , Expert Systems , Nuclear Magnetic Resonance, Biomolecular , Polycyclic Compounds/chemistry , Models, Molecular , Molecular Structure
7.
Org Lett ; 3(11): 1649-52, 2001 May 31.
Article in English | MEDLINE | ID: mdl-11405677

ABSTRACT

Enantioselective syntheses of the potent antifungal agent (-)-jesterone, its hydroxy epimer, and a dimeric quinone epoxide derivative are reported. The synthesis involves diastereoselective epoxidation of a chiral quinone monoketal derivative and regio- and stereoselective reduction of a quinone epoxide intermediate.


Subject(s)
Alkenes/chemical synthesis , Antifungal Agents/chemical synthesis , Epoxy Compounds/chemical synthesis , Antifungal Agents/chemistry , Crystallography, X-Ray , Indicators and Reagents , Models, Molecular , Stereoisomerism
8.
Org Lett ; 2(22): 3509-12, 2000 Nov 02.
Article in English | MEDLINE | ID: mdl-11082021

ABSTRACT

[reaction: see text] A new strategy for the synthesis and purification of synthetic intermediates is described using anthracene-tagged ester substrates in conjunction with an N-benzylmaleimide resin. Anthracene chemical tags permit use of standard solution-phase reaction conditions and reaction-monitoring techniques.


Subject(s)
Anthracenes/chemistry , Anthracenes/chemical synthesis , Esters/chemical synthesis , Esters/chemistry , Indicators and Reagents , Kinetics , Maleimides , Models, Molecular , Molecular Conformation , Molecular Structure , Resins, Plant , Structure-Activity Relationship
9.
Comb Chem High Throughput Screen ; 3(2): 93-102, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10788579

ABSTRACT

Increasing emphasis has recently been placed on the development of synthetic methods which effectively couple chemical synthesis and purification. For example, new formats for parallel synthesis are being developed which involve attachment of chemical tags to both reagents, reactants, and substrates to permit their chemoselective removal from reaction mixtures. The driving force for the development of tagged organic reagents is the ability to use standard solution-phase chemistry methods and reaction monitoring techniques (e.g. TLC and HPLC). In this mini-review, we will outline recent developments on the growing class of chemically tagged reagents, reactants, and substrates and highlight examples of their use in multistep synthesis.


Subject(s)
Combinatorial Chemistry Techniques/methods , Polymers/chemistry , Chromatography, Affinity/methods , Indicators and Reagents/chemistry , Models, Chemical , Molecular Structure , Resins, Plant
11.
Biotechnol Bioeng ; 71(1): 9-18, 2000.
Article in English | MEDLINE | ID: mdl-10629531

ABSTRACT

The tactical combination of classical product precipitation and subsequent modification of precipitated products using polymer-assisted transformations has been employed in the preparation of substituted 2-aminothiazole derivatives. 2-aminothiazoles were precipitated in parallel as hydrobromide monohydrate salts, directly redissolved, and reacted further using polymer-supported reagents to afford free-based 2-aminothiazoles, aminothiazoyloxamates, and aminothiazoylamides.


Subject(s)
Thiazoles/chemical synthesis , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Indicators and Reagents , Models, Molecular , Molecular Structure , Polymers , Resins, Plant , Thiazoles/chemistry
12.
Bioorg Med Chem Lett ; 9(2): 209-12, 1999 Jan 18.
Article in English | MEDLINE | ID: mdl-10021930

ABSTRACT

1,2,4-Oxadiazoles have been prepared in parallel using 1,1'-carbonyldiimidazole (CDI) as a reagent for both formation and cyclodehydration of O-acyl benzamidoximes. The use of CDI facilitates parallel purification of the oxadiazole products by simple liquid-liquid extraction and filtration.


Subject(s)
Imidazoles/chemistry , Oxadiazoles/chemical synthesis , Benzamidines/chemistry , Carboxylic Acids/chemistry , Oxadiazoles/isolation & purification
13.
Mol Divers ; 2(4): 197-206, 1997.
Article in English | MEDLINE | ID: mdl-9249755

ABSTRACT

Solid-phase organic synthesis is now a prevalent activity in drug discovery. In keeping with this keen interest is the need to develop reliable automated synthesis instrumentation as well as polymeric supports and linkers suitable for the full range of organic synthesis applications. In this paper, we review our activities in the development of new and enabling tools for automated chemical synthesis, including the following: (i) new solid supports such as ArgoGel (PS-PEG-based) and Argo-X203 (PS-based); and (ii) the Nautilus 2400 system, a fully closed and inert automated chemistry development workstation. Selected chemistry optimization and synthesis examples performed on the Nautilus and new solid supports will be described.


Subject(s)
Biochemistry/instrumentation , Biochemistry/methods , Resins, Plant/chemical synthesis , Automation , Indicators and Reagents , Magnetic Resonance Spectroscopy , Polyethylene Glycols/chemical synthesis , Polystyrenes/chemical synthesis , Time Factors
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