Document Detail


Targeting a regulatory element in human thymidylate synthase mRNA.
MedLine Citation:
PMID:  23143777     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Thymidylate synthase (TS) is a key enzyme in the biosynthesis of thymidine. The use of TS inhibitors in cancer chemotherapy suffers from resistance development in tumors through upregulation of TS expression. Autoregulatory translation control has been implicated with TS overexpression. TS binding at its own mRNA, which leads to sequestration of the start codon, is abolished when the enzyme forms an inhibitor complex, thereby relieving translation suppression. We have used the protein-binding site from the TS mRNA in the context of a bicistronic expression system to validate targeting the regulatory motif with stabilizing ligands that prevent ribosomal initiation. Stabilization of the RNA by mutations, which were studied as surrogates of ligand binding, suppresses translation of the TS protein. Compounds that stabilize the TS-binding RNA motif and thereby inhibit ribosomal initiation might be used in combination with existing TS enzyme-targeting drugs to overcome resistance development during chemotherapy.
Authors:
Nicholas D Brunn; Emily Garcia Sega; Melody B Kao; Thomas Hermann
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-11-09
Journal Detail:
Title:  Chembiochem : a European journal of chemical biology     Volume:  13     ISSN:  1439-7633     ISO Abbreviation:  Chembiochem     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-20     Completed Date:  2013-06-10     Revised Date:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  100937360     Medline TA:  Chembiochem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  2738-44     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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MeSH Terms
Descriptor/Qualifier:
Base Sequence
Genes, Reporter / genetics
Humans
Inverted Repeat Sequences / drug effects
Ligands
Nucleotide Motifs / drug effects
Peptides / metabolism
Protein Biosynthesis / drug effects
RNA Stability / drug effects
RNA, Messenger / chemistry,  genetics,  metabolism
Regulatory Sequences, Ribonucleic Acid / drug effects*
Small Molecule Libraries / metabolism,  pharmacology*
Thymidylate Synthase / genetics*
Grant Support
ID/Acronym/Agency:
CA132753/CA/NCI NIH HHS; R01 CA132753/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Ligands; 0/Peptides; 0/RNA, Messenger; 0/Regulatory Sequences, Ribonucleic Acid; 0/Small Molecule Libraries; EC 2.1.1.45/Thymidylate Synthase
Comments/Corrections

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


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