Abstract
Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Strategies to treat tumors have been developed in which tumor cells are targeted with drugs or gene-therapy vectors specifically activated under hypoxic conditions. Here we report a different approach, in which the normal transcriptional response to hypoxia is selectively disrupted. Our data indicate that specific blockade of the interaction of hypoxia-inducible factor with the CH1 domain of its p300 and CREB binding protein transcriptional coactivators leads to attenuation of hypoxia-inducible gene expression and diminution of tumor growth. Thus, disrupting the normal co-activational response to hypoxia may be a new and useful therapeutic strategy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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CREB-Binding Protein
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Cell Hypoxia / genetics*
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DNA-Binding Proteins / metabolism*
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E1A-Associated p300 Protein
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Gene Expression Regulation, Neoplastic*
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Genetic Therapy / methods
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mice
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Mice, Nude
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Neoplasms, Experimental / therapy*
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Neovascularization, Pathologic
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Nuclear Proteins / metabolism*
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Protein Binding
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Trans-Activators / metabolism*
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Transcription Factors*
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Transcription, Genetic
Substances
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DNA-Binding Proteins
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Trans-Activators
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Transcription Factors
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CREB-Binding Protein
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Crebbp protein, mouse
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E1A-Associated p300 Protein
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Ep300 protein, mouse