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1.
Cell Rep ; 20(10): 2408-2423, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28877474

RESUMO

Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.


Assuntos
Neoplasias Colorretais/genética , RNA Longo não Codificante/genética , Proteína Supressora de Tumor p53/genética , Apoptose/genética , Apoptose/fisiologia , Ciclo Celular/genética , Ciclo Celular/fisiologia , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Neoplasias Colorretais/metabolismo , Proteínas de Ligação a DNA , Proteína Semelhante a ELAV 1/genética , Proteína Semelhante a ELAV 1/metabolismo , Células HCT116 , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , RNA Longo não Codificante/fisiologia , Proteínas de Ligação a RNA , Fatores de Transcrição , Proteína Supressora de Tumor p53/metabolismo
2.
Oncotarget ; 6(34): 35247-62, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26497213

RESUMO

Despite advances in multimodal treatment, neuroblastoma (NB) is often fatal for children with high-risk disease and many survivors need to cope with long-term side effects from high-dose chemotherapy and radiation. To identify new therapeutic targets, we performed an siRNA screen of the druggable genome combined with a small molecule screen of 465 compounds targeting 39 different mechanisms of actions in four NB cell lines. We identified 58 genes as targets, including AURKB, in at least one cell line. In the drug screen, aurora kinase inhibitors (nine molecules) and in particular the AURKB-selective compound, barasertib, were the most discriminatory with regard to sensitivity for MYCN-amplified cell lines. In an expanded panel of ten NB cell lines, those with MYCN-amplification and wild-type TP53 were the most sensitive to low nanomolar concentrations of barasertib. Inhibition of the AURKB kinase activity resulted in decreased phosphorylation of the known target, histone H3, and upregulation of TP53 in MYCN-amplified, TP53 wild-type cells. However, both wild-type and TP53 mutant MYCN-amplified cell lines arrested in G2/M phase upon AURKB inhibition. Additionally, barasertib induced endoreduplication and apoptosis. Treatment of MYCN-amplified/TP53 wild-type neuroblastoma xenografts resulted in profound growth inhibition and tumor regression. Therefore, aurora B kinase inhibition is highly effective in aggressive neuroblastoma and warrants further investigation in clinical trials.


Assuntos
Aurora Quinase B/antagonistas & inibidores , Neuroblastoma/enzimologia , Neuroblastoma/terapia , Animais , Apoptose/fisiologia , Aurora Quinase B/genética , Aurora Quinase B/metabolismo , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular , Neuroblastoma/genética , Neuroblastoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Bibliotecas de Moléculas Pequenas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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