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1.
Cancer Res ; 66(6): 3096-105, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16540659

RESUMO

14-3-3 sigma is induced by tumor suppressor protein p53 in response to DNA damage. p53 can directly transactivate the expression of 14-3-3 sigma to cause a G(2) cell cycle arrest when cell DNA is damaged. The expression of 14-3-3 sigma protein is down-regulated in various tumors, but its function has not been fully established. Protein kinase B/Akt, a crucial regulator of oncogenic signal involved in cell survival and proliferation, is deregulated in many types of cancer. Akt activation can enhance p53 degradation, but its role in DNA damage response is not clear. Here, we show that Akt activation is diminished when p53 and 14-3-3 sigma is up-regulated in response to DNA damage. Evidence is provided that 14-3-3 sigma binds and inhibits Akt. In keeping with this concept, Akt-mediated cell survival is inhibited by 14-3-3 sigma. Significantly, we show that 14-3-3 sigma inhibits Akt-mediated cell growth, transformation, and tumorigenesis. Low expression of 14-3-3 sigma in human primary breast cancers correlates with Akt activation. These data provide an insight into Akt regulation and rational cancer gene therapy by identifying 14-3-3 sigma as a molecular regulator of Akt and as a potential anticancer agent for Akt-activated cancers.


Assuntos
Biomarcadores Tumorais/biossíntese , Transformação Celular Neoplásica/genética , Dano ao DNA/fisiologia , Exonucleases/biossíntese , Proteínas de Neoplasias/biossíntese , Proteína Oncogênica v-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteína Supressora de Tumor p53/biossíntese , Proteínas 14-3-3 , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Processos de Crescimento Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Ativação Enzimática , Exonucleases/genética , Exonucleases/metabolismo , Exorribonucleases , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Vison , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína Oncogênica v-akt/metabolismo , Ratos , Proteína Supressora de Tumor p53/genética
2.
Mol Cell Biol ; 23(20): 7096-107, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14517281

RESUMO

The 14-3-3 sigma (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3 sigma is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3 sigma was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3 sigma in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3 sigma has not yet been characterized. Here, we studied the link between 14-3-3 sigma activities and p53 regulation. We found that 14-3-3 sigma interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3 sigma expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3 sigma antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3 sigma facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3 sigma appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3 sigma inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3 sigma system. These results defined an important p53 regulatory loop and suggested that 14-3-3 sigma expression can be considered for therapeutic intervention in cancers.


Assuntos
Biomarcadores Tumorais/metabolismo , Exonucleases/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas 14-3-3 , Transporte Ativo do Núcleo Celular , Animais , Antibacterianos/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Northern Blotting , Western Blotting , Bromodesoxiuridina/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Dano ao DNA , Regulação para Baixo , Doxiciclina/farmacologia , Exorribonucleases , Feminino , Genes Reporter , Glutationa Transferase/metabolismo , Humanos , Luciferases/metabolismo , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Modelos Biológicos , Células NIH 3T3 , Testes de Precipitina , Ligação Proteica , Fatores de Tempo , Ubiquitina/metabolismo
3.
Nat Cell Biol ; 17(3): 311-21, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25686251

RESUMO

Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in microRNAs (miRNAs), its effects on tumour growth and metastasis are not well understood. We present evidence of CREB-mediated low expression of ADAR1 in metastatic melanoma cell lines and tumour specimens. Re-expression of ADAR1 resulted in the suppression of melanoma growth and metastasis in vivo. Consequently, we identified three miRNAs undergoing A-to-I editing in the weakly metastatic melanoma but not in strongly metastatic cell lines. One of these miRNAs, miR-455-5p, has two A-to-I RNA-editing sites. The biological function of edited miR-455-5p is different from that of the unedited form, as it recognizes a different set of genes. Indeed, wild-type miR-455-5p promotes melanoma metastasis through inhibition of the tumour suppressor gene CPEB1. Moreover, wild-type miR-455 enhances melanoma growth and metastasis in vivo, whereas the edited form inhibits these features. These results demonstrate a previously unrecognized role for RNA editing in melanoma progression.


Assuntos
Adenosina/metabolismo , Regulação Neoplásica da Expressão Gênica , Inosina/metabolismo , Melanoma/genética , Edição de RNA , Neoplasias Cutâneas/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Progressão da Doença , Feminino , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Nus , MicroRNAs , Dados de Sequência Molecular , Metástase Neoplásica , Transplante de Neoplasias , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
4.
Nat Commun ; 6: 7530, 2015 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-26179207

RESUMO

Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumorigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programmes by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anticancer metabolism therapy development in future.


Assuntos
Proteínas 14-3-3/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Metabolismo Energético/genética , Exorribonucleases/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas 14-3-3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Intervalo Livre de Doença , Exorribonucleases/metabolismo , Feminino , Técnicas de Inativação de Genes , Glutamina/metabolismo , Glicólise/genética , Células HCT116 , Humanos , Pessoa de Meia-Idade , Biogênese de Organelas , Prognóstico , Proteólise , Ubiquitinação/genética , Adulto Jovem
5.
J Med Virol ; 70(1): 109-18, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12629651

RESUMO

The cell tropism of enterovirus 71 (Enteroviridae) in neuronal, glial and laryngeal cells. The 4643 strain, an enterovirus 71 isolate from a patient in Taiwan, was used to infect three human cell lines representing neuronal cells (SK-N-SH, neuroblastoma), glial cells (U373MG, glioblastoma), and laryngeal cells (HEp-2, larynx epidermoid carcinoma). Immunofluorescent staining and transmission electron microscopy (TEM) were used to detect mature enterovirus 71 4643 virions in these cell lines. The three cell lines were also compared for presence of virus-mediated cytopathic effect (CPE), synthesis of infected cell-specific proteins, viral (-) RNA, and virus replication rate. Virus particles were detected by TEM, and viral replication increased over time, indicating the existence and release of mature viruses from all three infected cell lines. The most severe CPE and the highest viral replication rate were observed in the SK-N-SH cells. Further screening of the infected cell lines by microarray analysis revealed that the neuron growth factor receptor (NGFR) gene was uniquely upregulated in infected SK-N-SH cells, implying that the receptor encoded by this gene may be involved in cell tropism. The data show that neurons are vulnerable to enterovirus 71 4643 infection and are consistent with the clinical observation that enterovirus 71 4643 targets mainly neuronal cells but is also found in many organs in conjunction with an inflammatory reaction.


Assuntos
Enterovirus/fisiologia , Neurônios/virologia , Replicação Viral , Animais , Linhagem Celular , Chlorocebus aethiops , Efeito Citopatogênico Viral , Enterovirus/crescimento & desenvolvimento , Regulação Viral da Expressão Gênica , Humanos , Microscopia Eletrônica , Neuroglia , RNA Viral/biossíntese , Células Vero , Proteínas Virais/biossíntese , Cultura de Vírus
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