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P53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes.

ABSTRACT: The p53 tumor suppressor protein is a major sensor of cellular stresses, and upon stabilization, activates or represses many genes that control cell fate decisions. While the mechanism of p53-mediated transactivation is well established, several mechanisms have been proposed for p53-mediated repression. Here, we demonstrate that the cyclin-dependent kinase inhibitor p21 is both necessary and sufficient for the downregulation of known p53-repression targets, including survivin, CDC25C, and CDC25B in response to p53 induction. These same targets are similarly repressed in response to p16 overexpression, implicating the involvement of the shared downstream retinoblastoma (RB)-E2F pathway. We further show that in response to either p53 or p21 induction, E2F4 complexes are specifically recruited onto the promoters of these p53-repression targets. Moreover, abrogation of E2F4 recruitment via the inactivation of RB pocket proteins, but not by RB loss of function alone, prevents the repression of these genes. Finally, our results indicate that E2F4 promoter occupancy is globally associated with p53-repression targets, but not with p53 activation targets, implicating E2F4 complexes as effectors of p21-dependent p53-mediated repression.

SUBMITTER: Benson EK

PROVIDER: S-EPMC4067464 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes.

Benson E K EK Mungamuri S K SK Attie O O Kracikova M M Sachidanandam R R Manfredi J J JJ Aaronson S A SA

Oncogene 20131007 30

The p53 tumor suppressor protein is a major sensor of cellular stresses, and upon stabilization, activates or represses many genes that control cell fate decisions. While the mechanism of p53-mediated transactivation is well established, several mechanisms have been proposed for p53-mediated repression. Here, we demonstrate that the cyclin-dependent kinase inhibitor p21 is both necessary and sufficient for the downregulation of known p53-repression targets, including survivin, CDC25C, and CDC25B ...[more]

PMID: 24096481

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Project description:The devastating prognosis of hepatocellular carcinoma (HCC) is partially attributed to chemotherapy resistance. Accumulating evidence suggests that the epithelial-mesenchymal transition (EMT) is a key driving force of carcinoma metastasis and chemoresistance in solid tumors. Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), as an EMT inducer, is involved in the potentiation of Wnt signaling in HCC. This study proposes uncovering the roles of Lgr5 in Doxorubicin (Dox) resistance of HCC to improve treatment efficacy for HCC. Methods: We investigated the expression and significance of Lgr5 in HCC tissue and different cell lines. The effect of Lgr5 in EMT and Dox resistance was analyzed in HCC cells and implanted HCC tumor models. A two-hybrid analysis, using the Lgr5 gene as the bait and a HCC cDNA library, was used to screen targeted proteins that interact with Lgr5. The positive clones were identified by coimmunoprecipitation (Co-IP) and Glutathione-S-transferase (GST) pull-down. The impact of the interaction on Dox resistance was investigated by a series of assays in vitro and in vivo . Result: We found that Lgr5 was upregulated and positively correlated with poor prognosis in HCC. Additionally, it functioned as a tumor promoter to increase cell migration and induce EMT in HCC cells and increase the resistance to Dox. We identified programmed cell death protein 5 (PDCD5) as a target gene of Lgr5 and we found that PDCD5 was responsible for Lgr5-mediated Dox resistance. Further analysis with Co-IP and GST pull-down assays showed that the N-terminal extracellular domain of Lgr5 could directly bind to PDCD5. Lgr5 induced p53 degradation by blocking the nuclear translocation of PDCD5 and leading to the loss of p53 stabilization. Lgr5 showed a protection against the inhibition of Dox on the growth of tumor subcutaneously injected. Moreover, Lgr5 suppressed Dox-induced apoptosis via the p53 pathway and attenuated the cytotoxicity of Dox to HCC. Conclusion: Lgr5 induces the EMT and inhibits apoptosis, thus promoting chemoresistance by regulating the PDCD5/p53 signaling axis. Furthermore, Lgr5 may be a potential target gene for overcoming Dox resistance.

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P53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes.

Publications

p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes.

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