title: Targeting a regulatory element in human thymidylate synthase mRNA.
abstract: 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.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, 92093, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Brunn
authors.forename: Emily
authors.initials: E
authors.lastname: Garcia Sega
authors.forename: Melody B
authors.initials: MB
authors.lastname: Kao
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermann
mesh_terms: D001483:Base Sequence; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D055029:Inverted Repeat Sequences / Q000187:drug effects; D008024:Ligands; D059372:Nucleotide Motifs / Q000187:drug effects; D010455:Peptides / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D038621:Regulatory Sequences, Ribonucleic Acid / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D008024:Ligands; D010455:Peptides; D012333:RNA, Messenger; D038621:Regulatory Sequences, Ribonucleic Acid; D054852:Small Molecule Libraries; D013940:Thymidylate Synthase