title: Genomic effects of polyamide/DNA interactions on mRNA expression.
abstract: Here we characterize the biological activity of a hairpin polyamide 1 that inhibits binding of the minor-groove transcription factor LEF-1, constitutively expressed in colon cancers. Genome-wide analysis of mRNA expression in DLD1 colon cancer cells treated with 1 reveals that a limited number of genes are affected; the most significant changes correspond to genes related to cell cycle, signaling, and proteolysis rather than the anticipated WNT signaling pathway. Treated cells display increased doubling time and hypersensitivity to DNA damage that most likely results from downregulation of DNA-damage checkpoint genes, including YWAE (14-3-3epsilon protein) and DDIT3. Promoter analyses on a genomic level revealed numerous potential polyamide binding sites and multiple possible mechanisms for transcriptional antagonism, underscoring the utility of gene expression profiling in understanding the effects of polyamides on transcription at the cellular level.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Lubica
authors.initials: L
authors.lastname: Supekova
authors.forename: John Paul
authors.initials: JP
authors.lastname: Pezacki
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Su
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Loweth
authors.forename: Rainer
authors.initials: R
authors.lastname: Riedl
authors.forename: Bernhard
authors.initials: B
authors.lastname: Geierstanger
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: David E
authors.initials: DE
authors.lastname: Wemmer
mesh_terms: D001665:Binding Sites; D037282:Calreticulin / Q000235:genetics; D003110:Colonic Neoplasms; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D030541:Databases, Genetic; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D019940:Genes, bcl-1 / Q000235:genetics; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008856:Microscopy, Fluorescence; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000737:chemistry / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis*; D014157:Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D037282:Calreticulin; D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D009757:Nylons; D012333:RNA, Messenger; D014157:Transcription Factors; D004247:DNA