Arsenic Suppresses Cell Survival via Pirh2-mediated Proteasomal Degradation of ΔNp63 Protein

Yan, Wensheng; Chen, Xiufang; Zhang, Yanhong; Zhang, Jin; Jung, Yong Sam; Chen, Xinbin

doi:10.1074/jbc.m112.428607

Cited by 17 publications

(18 citation statements)

References 52 publications

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“…Therefore, we focused on E3 ubiquitin ligases reported to target ΔNp63: Fbw7 (Galli et al, 2010; Restelli et al, 2014), Itch (Rossi et al, 2006a; Rossi et al, 2006b), HDM2 (Galli et al, 2010), Pirh2 (Jung et al, 2013; Yan et al, 2013), and WWP1 (Li et al, 2008). Colo16 cells were transfected with siRNAs against each of these factors individually and treated with the HDACi, JNJ-26481585, or the vehicle alone, DMSO.…”

Section: Resultsmentioning

confidence: 99%

ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer

et al. 2016

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SUMMARY ΔNp63 is an oncogenic member of the p53 family and acts to inhibit the tumor suppressive activities of the p53 family. By performing a chemical library screen, we identified HDAC inhibitors (HDACi) as agents reducing ΔNp63 protein stability through the E3 ubiquitin ligase, Fbw7. ΔNp63 inhibition decreases the levels of its transcriptional target, DGCR8, and the maturation of let-7d and miR-128, which we found critical for HDACi function in vitro and in vivo. Our work identified Fbw7 as a predictive marker for HDACi response in squamous cell carcinomas and lymphomas and unveiled let-7d and miR-128 as specific targets to bypass tumor resistance to HDACi treatment.

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Section: Resultsmentioning

confidence: 99%

ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer

et al. 2016

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“…1C–D, ΔNp63α panels). Furthermore, we tested whether RBM24 has an effect on TAp63 expression by using MIA-PaCa2 cells, in which TAp63α is highly expressed (27). We found that the level of TAp63α protein was markedly decreased by ectopic expression of RBM24 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…HaCaT, ME180, MIA-PaCa2, MCF10A, HCT116, and MCF7 cells were cultured in DMEM supplemented with 10% fetal bovine serum as previously described (18, 27). MEFs were cultured in DMEM supplemented with 10% fetal bovine serum, 1x nonessential amino acids, and 55 μM beta-mercaptoethanol.…”

Section: Methodsmentioning

confidence: 99%

RNA-Binding Protein RBM24 Regulates p63 Expression via mRNA Stability

Zhang

et al. 2014

Molecular Cancer Research

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P63, a p53 family member, plays pivotal roles in epidermal development, aging, and tumorigenesis. Thus, understanding how p63 expression is controlled has biological and clinical importance. RBM24 is an RNA-binding protein and shares a high sequence similarity with RBM38, a critical regulator of p63. In the current study, we investigated whether RBM24 is capable of regulating p63 expression. Indeed, we found that ectopic expression of RBM24 decreased, whereas knockdown of RBM24 increased, the levels of p63 transcript and protein. To explore the underlying mechanism, we found that RBM24 was able to bind to multiple regions in the p63 3′ untranslated region and subsequently, destabilize p63 transcript. Furthermore, we showed that the 3′ untranslated region in p63 transcript and the RNA-binding domain in RBM24 were required for RBM24 to bind p63 transcript and consequently, inhibit p63 expression. Taken together, our data provide evidence that RBM24 is a novel regulator of p63 via mRNA stability. Implications Our study suggests that p63 is regulated by RBM24 via mRNA stability, which gives an insight into understanding how posttranscriptional regulatory mechanisms contribute to p63 expression.

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“…Previously, we found that arsenic induces expression of Pirh2 E3 ligase to degrade ΔNp63 oncogenic protein, a member of the p53 family [34]. Pirh2 is known to be an E3 ligase targeting wild-type p53 protein for degradation [42], [43].…”

Section: Resultsmentioning

confidence: 99%

Arsenic Trioxide Reactivates Proteasome-Dependent Degradation of Mutant p53 Protein in Cancer Cells in Part via Enhanced Expression of Pirh2 E3 Ligase

et al. 2014

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The p53 gene is mutated in more than 50% of human tumors. Mutant p53 exerts an oncogenic function and is often highly expressed in cancer cells due to evasion of proteasome-dependent degradation. Thus, reactivating proteasome-dependent degradation of mutant p53 protein is an attractive strategy for cancer management. Previously, we found that arsenic trioxide (ATO), a drug for acute promyelocytic leukemia, degrades mutant p53 protein through a proteasome pathway. However, it remains unclear what is the E3 ligase that targets mutant p53 for degradation. In current study, we sought to identify an E3 ligase necessary for ATO-mediated degradation of mutant p53. We found that ATO induces expression of Pirh2 E3 ligase at the transcriptional level. We also found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, ATO-induced degradation of mutant p53 protein. Furthermore, we found that Pirh2 E3 ligase physically interacts with and targets mutant p53 for polyubiquitination and subsequently proteasomal degradation. Interestingly, we found that ATO cooperates with HSP90 or HDAC inhibitor to promote mutant p53 degradation and growth suppression in tumor cells. Together, these data suggest that ATO promotes mutant p53 degradation in part via induction of the Pirh2-dependent proteasome pathway.

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Arsenic Suppresses Cell Survival via Pirh2-mediated Proteasomal Degradation of ΔNp63 Protein

Cited by 17 publications

References 52 publications

ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer

ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer

RNA-Binding Protein RBM24 Regulates p63 Expression via mRNA Stability

Arsenic Trioxide Reactivates Proteasome-Dependent Degradation of Mutant p53 Protein in Cancer Cells in Part via Enhanced Expression of Pirh2 E3 Ligase

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