Small-Molecule Activation Of P53 Blocks Hypoxia-Inducible Factor 1 Alpha And Vascular Endothelial Growth Factor Expression In Vivo And Leads To Tumor Cell Apoptosis In Normoxia And Hypoxia
MOLECULAR AND CELLULAR BIOLOGY(2009)
摘要
The p53 tumor suppressor protein negatively regulates hypoxia-inducible factor 1 alpha (HIF-1 alpha). Here, we show that induction of p53 by the small-molecule RITA (reactivation of p53 and induction of tumor cell apoptosis) [2,5-bis(5-hydroxymethyl-2-thienyl) furan] (NSC-652287) inhibits HIF-1 alpha and vascular endothelial growth factor expression in vivo and induces significant tumor cell apoptosis in normoxia and hypoxia in p53-positive cells. RITA has been proposed to stabilize p53 by inhibiting the p53-HDM2 interaction. However, induction of p53 alone was insufficient to block HIF-1 alpha induced in hypoxia and has previously been shown to require additional stimuli, such as DNA damage. Here, we identify a new mechanism of action for RITA: RITA activates a DNA damage response, resulting in phosphorylation of p53 and gamma H2AX in vivo. Unlike other DNA damage response-inducing agents, RITA treatment of cells induced a p53-dependent increase in phosphorylation of the alpha subunit of eukaryotic initiation factor 2, requiring PKR-like endoplasmic reticulum kinase activity, and led to the subsequent downregulation of HIF-1 alpha and p53 target proteins, including HDM2 and p21. Through the identification of a new mechanism of action for RITA, our study uncovers a novel link between the DNA damage response-p53 pathway and the protein translational machinery.
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关键词
vascular endothelial growth factor a,vascular endothelial growth factor,dna repair,dna damage,apoptosis,histones,phosphorylation,endoplasmic reticulum
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