Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway.
Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation by the CBP and p300 transcriptional coactivators. Through a target-based high-throughput screen, we identified chetomin as a disrupter of HIF binding to p300. At a molecular level, chetomin disrupts ... the structure of the CH1 domain of p300 and precludes its interaction with HIF, thereby attenuating hypoxia-inducible transcription. Systemic administration of chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth. These results demonstrate a therapeutic window for pharmacological attenuation of HIF activity and further establish the feasibility of disrupting a signal transduction pathway by targeting the function of a transcriptional coactivator with a small molecule.
Mesh Terms:
Animals, Anti-Bacterial Agents, Aryl Hydrocarbon Receptor Nuclear Translocator, Carcinoma, Hepatocellular, Cell Hypoxia, Colonic Neoplasms, DNA-Binding Proteins, Disulfides, E1A-Associated p300 Protein, Erythropoietin, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Indole Alkaloids, Liver Neoplasms, Luciferases, Male, Mice, Mice, Nude, Nuclear Proteins, Prostatic Neoplasms, Protein Binding, Receptors, Aryl Hydrocarbon, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic, Transplantation, Heterologous, Vascular Endothelial Growth Factor A
Animals, Anti-Bacterial Agents, Aryl Hydrocarbon Receptor Nuclear Translocator, Carcinoma, Hepatocellular, Cell Hypoxia, Colonic Neoplasms, DNA-Binding Proteins, Disulfides, E1A-Associated p300 Protein, Erythropoietin, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Indole Alkaloids, Liver Neoplasms, Luciferases, Male, Mice, Mice, Nude, Nuclear Proteins, Prostatic Neoplasms, Protein Binding, Receptors, Aryl Hydrocarbon, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic, Transplantation, Heterologous, Vascular Endothelial Growth Factor A
Cancer Cell
Date: Jul. 01, 2004
PubMed ID: 15261140
View in: Pubmed Google Scholar
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