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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Negative regulation of the p300-p53 interplay by DDX24
1Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
Abstract:
Numerous studies indicate that p300 acts as a key transcriptional cofactor in vivo, at least, in part, by modulating activities of p53 by acetylation. Nevertheless, the regulation of the p53-p300 interplay is not completely understood. Here, we have identified the DEAD (Asp-Glu-Ala-Asp) box RNA helicase 24 (DDX24) as a novel regulator of the p300-p53 axis. We found that DDX24 interacts with p300, and this interaction leads to suppression of p300-mediated acetylation of p53. Notably, RNA interference-mediated knockdown of endogenous DDX24 significantly increases the acetylation levels of endogenous p53 in human cancer cells and subsequently promotes p53-mediated activation of its transcriptional targets such as p21 and p53 upregulated modulator of apoptosis (PUMA). In contrast, DDX24 expression inhibits the p300-p53 interaction and suppresses p300-mediated acetylation of p53. Moreover, DDX24 is overexpressed in human cancer cells and reduction of DDX24 protein levels by RNA interference induces cell cycle arrest and senescence in a p53-dependent manner. These results reveal DDX24 as an important regulator of p300 and suggest that the modulation of the p53-p300 interplay by DDX24 is critical in controlling p53 activities in human cancer cells.
Insights
DEAD box RNA helicase 24 (DDX24) regulates the p53-p300 interaction, impacting cancer cell growth. DDX24 suppresses p53 acetylation, and its knockdown promotes p53-dependent cell cycle arrest and senescence.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- p300 is a key transcriptional cofactor modulating p53 activity via acetylation.
- The precise regulation of the p53-p300 interaction remains incompletely understood.
Purpose of the Study:
- To identify novel regulators of the p53-p300 interplay.
- To investigate the role of DEAD box RNA helicase 24 (DDX24) in p53 acetylation and cancer cell biology.
Main Methods:
- Investigated DDX24 interaction with p300 using co-immunoprecipitation.
- Utilized RNA interference to knockdown DDX24 in human cancer cells.
- Assessed p53 acetylation levels and expression of p53 target genes (p21, PUMA).
- Examined the effect of DDX24 modulation on cell cycle arrest and senescence.
Main Results:
- DDX24 directly interacts with p300, suppressing p300-mediated p53 acetylation.
- Knockdown of DDX24 increases endogenous p53 acetylation, enhancing p53 target gene activation.
- DDX24 overexpression inhibits p53-p300 interaction and p53 acetylation.
- DDX24 is overexpressed in human cancers; its reduction induces p53-dependent cell cycle arrest and senescence.
Conclusions:
- DDX24 is a novel regulator of the p53-p300 axis.
- DDX24's modulation of p53 acetylation is critical for controlling p53 activity in human cancer cells.
- DDX24 represents a potential therapeutic target in cancer treatment.
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