Abstract:
: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.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Kung AL,Zabludoff SD,France DS,Freedman SJ,Tanner EA,Vieira A,Cornell-Kennon S,Lee J,Wang B,Wang J,Memmert K,Naegeli HU,Petersen F,Eck MJ,Bair KW,Wood AW,Livingston DMdoi
10.1016/j.ccr.2004.06.009keywords:
subject
Has Abstractpub_date
2004-07-01 00:00:00pages
33-43issue
1eissn
1535-6108issn
1878-3686pii
S153561080400176Xjournal_volume
6pub_type
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