Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MDM2 mediates the ubiquitylation and thereby triggers the proteasomal degradation of the tumor suppressor protein p53. However, genetic evidence suggests that MDM2 contributes to multiple regulatory networks independently of p53 degradation. We have now identified the DEAD-box RNA helicase DDX24 as a nucleolar protein that interacts with MDM2. DDX24 was found to bind to the central region of MDM2, resulting in the polyubiquitylation of DDX24 both in vitro and in vivo. Unexpectedly, however, the polyubiquitylation of DDX24 did not elicit its proteasomal degradation but rather promoted its association with preribosomal ribonucleoprotein (pre-rRNP) processing complexes that are required for the early steps of pre-rRNA processing. Consistently with these findings, depletion of DDX24 in cells impaired pre-rRNA processing and resulted both in abrogation of MDM2 function and in consequent p53 stabilization. Our results thus suggest an unexpected role of MDM2 in the nonproteolytic ubiquitylation of DDX24, which may contribute to the regulation of pre-rRNA processing.
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PMID:MDM2 mediates nonproteolytic polyubiquitylation of the DEAD-Box RNA helicase DDX24. 2498 Apr 33

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.
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PMID:Negative regulation of the p300-p53 interplay by DDX24. 2586 71

Targeted cancer therapeutics aim to exploit tumor-specific, genetic vulnerabilities specifically affecting neoplastic cells without similarly affecting normal cells. Here we performed sequencing-based screening of an shRNA library on a panel of cancer cells of different origins as well as normal cells. The shRNA library was designed to target a subset of genes previously identified using a whole genome screening approach. This focused shRNA library was infected into cells followed by analysis of enrichment and depletion of the shRNAs over the course of cell proliferation. We developed a bootstrap likelihood ratio test for the interpretation of the effects of multiple shRNAs over multiple cell line passages. Our analysis identified 44 genes whose depletion preferentially inhibited the growth of cancer cells. Among these genes ribosomal protein RPL35A, putative RNA helicase DDX24, and coatomer complex I (COPI) subunit ARCN1 most significantly inhibited growth of multiple cancer cell lines without affecting normal cell growth and survival. Further investigation revealed that the growth inhibition caused by DDX24 depletion is independent of p53 status underlining its value as a drug target. Overall, our study establishes a new approach for the analysis of proliferation-based shRNA selection strategies and identifies new targets for the development of cancer therapeutics.
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PMID:Identification of novel cancer therapeutic targets using a designed and pooled shRNA library screen. 2822 11