期刊
CANCER CELL
卷 15, 期 5, 页码 441-453出版社
CELL PRESS
DOI: 10.1016/j.ccr.2009.03.021
关键词
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资金
- Swedish Cancer Society
- Swedish Research Council
- Cancer Society of Stockholm
- Lars-Hiertas Minne Foundation
- Robert Lundberg's memorial foundation
- Lindhes Advokatbyra AB
- European Commission FP6
Targeting oncogene addiction is a promising strategy for anticancer therapy. We report a potent inhibition of crucial oncogenes by p53 upon reactivation by small-molecule RITA in vitro and in vivo. RITA-activated p53 unleashes the transcriptional repression of antiapoptotic proteins Mcl-1, Bcl-2, MAP4, and survivin; blocks the Akt pathway on several levels; and downregulates c-Myc, cyclin E, and beta-catenin. p53 ablates c-Myc expression via several mechanisms at the transcriptional and posttranscriptional level. We show that the threshold for p53-mediated transrepression of survival genes is higher than for transactivation of proapoptotic targets. Inhibition of oncogenes by p53 reduces the cell's ability to buffer proapoptotic signals and elicits robust apoptosis. Our study highlights the role of transcriptional repression for p53-mediated tumor suppression.
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