title: Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface.
abstract: Transcription mediated by hypoxia-inducible factor (HIF-1) contributes to tumor angiogenesis and metastasis but is also involved in activation of cell-death pathways and normal physiological processes. Given the complexity of HIF-1 signaling, it could be advantageous to target a subset of HIF-1 effectors rather than the entire pathway. We compare the genome-wide effects of three molecules that each interfere with the HIF-1-DNA interaction: a polyamide targeted to the hypoxia response element, small interfering RNA targeted to HIF-1alpha, and echinomycin, a DNA-binding natural product with a similar but less specific sequence preference than the polyamide. The polyamide affects a subset of hypoxia-induced genes consistent with its binding site preferences. For comparison, HIF-1alpha siRNA and echinomycin each affect the expression of nearly every gene induced by hypoxia. Remarkably, the total number of genes affected by either polyamide or HIF-1alpha siRNA over a range of thresholds is comparable. The data show that polyamides can be used to affect a subset of a pathway regulated by a transcription factor. In addition, this study offers a unique comparison of three complementary approaches towards exogenous control of endogenous gene expression.
authors: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors: Nicholas G
authors: NG
authors: Nickols
authors: Claire S
authors: CS
authors: Jacobs
authors: Michelle E
authors: ME
authors: Farkas
authors: Peter B
authors: PB
authors: Dervan
mesh_terms: D001483:Base Sequence; D016923:Cell Death; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D019802:Succinic Acid / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051793:Hypoxia-Inducible Factor 1; D004247:DNA; D019802:Succinic Acid
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