Triplex formation at the rat neu oncogene promoter.
Current cancer chemotherapy treatments generally act by affecting rapidly growing malignant cells. Unfortunately, they are relatively nonspecific and thus have a tendency to affect other rapidly growing normal cells in a deleterious manner. Triplex-forming oligodeoxyribonucleotides (TFOs) promise to be a new class of sequence-specific DNA-binding drugs which will target malignancies at the transcriptional level. The formation of an intermolecular triplex (triple helix) has been shown to block the binding of transcription factors and repress transcription in genes such as c-myc and that encoding the epidermal growth factor receptor. The rat neu oncogene promoter contain promoter-enhancer elements which are purine/pyrimidine rich. These enhancer elements are amenable to targeting by TFOs. the human counterpart of rat neu, HER2, is often found to be amplified or overexpressed in a variety of malignancies, such as those of the breast, lungs, ovary, colon and stomach. TFOs may proved to be the basis of effective chemotherapy drugs for these cancers. TFO binding at the "GTG" element (5'GGTGGGGGGG) and at the 'GA' element (5'GGAGGAGGAGGG) has been characterized by gel mobility shift analysis and DNase 1 footprinting. Binding has been shown to occur at a Kd as low as 10(-8) M and has been shown to be sequence specific.
Center for Biotechnology, Baylor College of Medicine, The Woodlands, TX 77381.
J E
JE
Gee
R L
RL
Yen
M C
MC
Hung
M E
ME
Hogan
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D003850:Deoxyribonuclease I; D018734:Genes, erbB-2; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats
D009838:Oligodeoxyribonucleotides; D004247:DNA; D003850:Deoxyribonuclease I