Document Detail


GeneBlocs are powerful tools to study and delineate signal transduction processes that regulate cell growth and transformation.
MedLine Citation:
PMID:  12162696     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The study of signal transduction processes using antisense oligonucleotides is often complicated by low intracellular stability of the antisense reagents or by nonspecific effects that cause toxicity. Here, we introduce a new class of antisense molecules, so-called GeneBlocs, which are characterized by improved stability, high target RNA specificity, and low toxicity. GeneBlocs allow for efficient downregulation of mRNA expression at nanomolar concentrations, and they do not interfere with cell proliferation. We demonstrate these beneficial properties using a positive readout system. GeneBloc-mediated inhibition of tumor suppressor PTEN (phosphatase and tension homologue detected on chromosome 10) expression leads to hyperactivation of the phosphatidylinositol (PI) 3-kinase pathway, thereby mimicking the loss of PTEN function and its early consequences observed in mammalian cancer cells. Specifically, cells treated with PTEN GeneBlocs show functional activation of Akt, a downstream effector of PI 3-kinase signaling, and exhibit enhanced proliferation when seeded on a basement membrane matrix. In addition, GeneBlocs targeting the catalytic subunit of PI 3-kinase, p110, specifically inhibit signal transduction of endogenous or recombinant PI 3-kinase. This demonstrates that GeneBlocs are powerful tools to analyze and to modulate signal transduction processes and, therefore, represent alternative reagents for the validation of gene function.
Authors:
Maria Sternberger; Anett Schmiedeknecht; Anny Kretschmer; Frank Gebhardt; Frauke Leenders; Frank Czauderna; Ira Von Carlowitz; Mike Engle; Klaus Giese; Leonid Beigelman; Anke Klippel
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Antisense & nucleic acid drug development     Volume:  12     ISSN:  1087-2906     ISO Abbreviation:  Antisense Nucleic Acid Drug Dev.     Publication Date:  2002 Jun 
Date Detail:
Created Date:  2002-08-06     Completed Date:  2003-01-22     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9606142     Medline TA:  Antisense Nucleic Acid Drug Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  131-43     Citation Subset:  IM    
Affiliation:
atugen AG, Berlin, Germany.
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MeSH Terms
Descriptor/Qualifier:
1-Phosphatidylinositol 3-Kinase / metabolism
Animals
Apoptosis / radiation effects
Base Sequence
Cell Division / genetics,  physiology*
Cell Line
Cell Transformation, Neoplastic / genetics*
Enzyme Activation
Gene Expression
Genetic Techniques*
Humans
Oligonucleotides, Antisense / chemistry*,  pharmacology
PTEN Phosphohydrolase
Phosphoric Monoester Hydrolases / antagonists & inhibitors*,  genetics
Phosphorylation
Rats
S Phase / drug effects
Signal Transduction / genetics,  physiology*
Tumor Suppressor Proteins / antagonists & inhibitors*,  genetics
Ultraviolet Rays
Chemical
Reg. No./Substance:
0/Oligonucleotides, Antisense; 0/Tumor Suppressor Proteins; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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