Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 29, Issue 8, Pages 2243-2253Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00959-08
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Funding
- University College London
- The Institute of Cancer Research, United Kingdom
- Cancer Research United Kingdom (CUK) program [C309/A2187, C7358/A4420, C7358/A8020, C7358/A9958]
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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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