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1.
Nat Commun ; 12(1): 4878, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385447

RESUMO

A postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPß, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fatores de Iniciação de Peptídeos/genética , Biossíntese de Proteínas/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Clofazimina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Inativação Gênica , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Fatores de Iniciação de Peptídeos/antagonistas & inibidores , Fatores de Iniciação de Peptídeos/metabolismo
2.
Cancer Cell ; 39(1): 68-82.e9, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33186519

RESUMO

Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by PTEN deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.


Assuntos
Docetaxel/administração & dosagem , Deleção de Genes , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/patologia , Inibidor Tecidual de Metaloproteinase-1/genética , Animais , Senescência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo
4.
Nat Genet ; 50(2): 219-228, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29335542

RESUMO

The mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus. Whereas nuclear PDC controls the expression of sterol regulatory element-binding transcription factor (SREBF)-target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated manner, thereby sustaining anabolism. Additionally, we found that PDHA1 and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1) are frequently amplified and overexpressed at both the gene and protein levels in prostate tumors. Together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy.


Assuntos
Compartimento Celular/fisiologia , Lipogênese , Neoplasias da Próstata/metabolismo , Piruvato Desidrogenase (Lipoamida)/genética , Complexo Piruvato Desidrogenase/fisiologia , Animais , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Células Cultivadas , Citoplasma/genética , Citoplasma/metabolismo , Citoplasma/patologia , Humanos , Lipogênese/genética , Masculino , Camundongos , Camundongos Knockout , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Processamento de Proteína Pós-Traducional/genética , Piruvato Desidrogenase (Lipoamida)/metabolismo , Complexo Piruvato Desidrogenase/metabolismo
5.
Cell Rep ; 21(6): 1507-1520, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29117557

RESUMO

Regular endurance training improves muscle oxidative capacity and reduces the risk of age-related disorders. Understanding the molecular networks underlying this phenomenon is crucial. Here, by exploiting the power of computational modeling, we show that endurance training induces profound changes in gene regulatory networks linking signaling and selective control of translation to energy metabolism and tissue remodeling. We discovered that knockdown of the mTOR-independent factor Eif6, which we predicted to be a key regulator of this process, affects mitochondrial respiration efficiency, ROS production, and exercise performance. Our work demonstrates the validity of a data-driven approach to understanding muscle homeostasis.


Assuntos
Fatores de Iniciação em Eucariotos/metabolismo , Exercício Físico , Músculo Esquelético/metabolismo , Acetilação , Animais , Calorimetria , Cromatografia Líquida de Alta Pressão , Regulação para Baixo , Metabolismo Energético/fisiologia , Fatores de Iniciação em Eucariotos/deficiência , Fatores de Iniciação em Eucariotos/genética , Redes Reguladoras de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Oxigênio/metabolismo , Condicionamento Físico Animal , Proteoma/análise , Espécies Reativas de Oxigênio/metabolismo , Ribossomos/metabolismo , Espectrometria de Massas em Tandem , Transcrição Genética , Regulação para Cima
6.
Dev Comp Immunol ; 77: 69-76, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28743432

RESUMO

Eukaryotic Initiation Factor 6 (eIF6) is required for 60S ribosomal subunit biogenesis and efficient initiation of translation. Intriguingly, in both mice and humans, endogenous levels of eIF6 are detrimental as they act as tumor and obesity facilitators, raising the question on the evolutionary pressure that maintains high eIF6 levels. Here we show that, in mice and humans, high levels of eIF6 are required for proper immune functions. First, eIF6 heterozygous (het) mice show an increased mortality during viral infection and a reduction of peripheral blood CD4+ Effector Memory T cells. In human CD4+ T cells, eIF6 levels rapidly increase upon T-cell receptor activation and drive the glycolytic switch and the acquisition of effector functions. Importantly, in CD4+ T cells, eIF6 levels control interferon-γ (IFN-γ) secretion without affecting proliferation. In conclusion, the immune system has a high evolutionary pressure for the maintenance of a dynamic and powerful regulation of the translational machinery.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fatores de Iniciação em Eucariotos/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Viroses/imunologia , Animais , Células Cultivadas , Fatores de Iniciação em Eucariotos/genética , Glicólise , Homeostase , Humanos , Sistema Imunitário , Memória Imunológica , Interferon gama/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Iniciação de Peptídeos/genética , Transdução de Sinais
7.
Biochem Soc Trans ; 44(6): 1667-1673, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27913676

RESUMO

Over the past few years, there has been a growing interest in the interconnection between translation and metabolism. Important oncogenic pathways, like those elicited by c-Myc transcription factor and mTOR kinase, couple the activation of the translational machinery with glycolysis and fatty acid synthesis. Eukaryotic initiation factor 6 (eIF6) is a factor necessary for 60S ribosome maturation. eIF6 acts also as a cytoplasmic translation initiation factor, downstream of growth factor stimulation. eIF6 is up-regulated in several tumor types. Data on mice models have demonstrated that eIF6 cytoplasmic activity is rate-limiting for Myc-induced lymphomagenesis. In spite of this, eIF6 is neither transcriptionally regulated by Myc, nor post-transcriptionally regulated by mTOR. eIF6 stimulates a glycolytic and fatty acid synthesis program necessary for tumor growth. eIF6 increases the translation of transcription factors necessary for lipogenesis, such as CEBP/ß, ATF4 and CEBP/δ. Insulin stimulation leads to an increase in translation and fat synthesis blunted by eIF6 deficiency. Paradoxycally, long-term inhibition of eIF6 activity increases insulin sensitivity, suggesting that the translational activation observed upon insulin and growth factors stimulation acts as a feed-forward mechanism regulating lipid synthesis. The data on the role that eIF6 plays in cancer and in insulin sensitivity make it a tempting pharmacological target for cancers and metabolic diseases. We speculate that eIF6 inhibition will be particularly effective especially when mTOR sensitivity to rapamycin is abrogated by RAS mutations.


Assuntos
Fatores de Iniciação de Peptídeos/genética , Biossíntese de Proteínas , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Camundongos , Modelos Genéticos , Neoplasias/genética , Neoplasias/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo
8.
Oncotarget ; 6(35): 37471-85, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26462016

RESUMO

eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCß axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eµ-Myc mouse lymphoma model, with lifespans extended up to 18 months. Here we screen for eIF6 expression in human cancers. We show that Malignant Pleural Mesothelioma tumors (MPM) and a MPM cell line (REN cells) contain high levels of hyperphosphorylated eIF6. Enzastaurin is a PKC beta inhibitor used in clinical trials. We prove that Enzastaurin treatment decreases eIF6 phosphorylation rate, but not eIF6 protein stability. The growth of REN, in vivo, and metastasis are reduced by either Enzastaurin treatment or eIF6 shRNA. Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells. Less glycolysis and less ATP content are evident in REN cells depleted for eIF6 or treated with Enzastaurin (Anti-Warburg effect). We propose that eIF6 is necessary for malignant mesothelioma growth, in vivo, and can be targeted by kinase inhibitors.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Fatores de Iniciação em Eucariotos/metabolismo , Mesotelioma/metabolismo , Neoplasias Pleurais/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Fatores de Iniciação em Eucariotos/genética , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Indóis/farmacologia , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma/terapia , Camundongos Endogâmicos NOD , Camundongos SCID , Fosforilação , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Proteína Quinase C beta/antagonistas & inibidores , Proteína Quinase C beta/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estabilidade Proteica , Interferência de RNA , Terapêutica com RNAi , Transdução de Sinais , Fatores de Tempo , Transfecção , Carga Tumoral , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nat Commun ; 6: 8261, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26383020

RESUMO

Insulin regulates glycaemia, lipogenesis and increases mRNA translation. Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin. The role of insulin-regulated translation is unknown. Here we show that reduction of insulin-regulated translation in mice heterozygous for eIF6 results in normal glycaemia, but less blood cholesterol and triglycerides. eIF6 controls fatty acid synthesis and glycolysis in a cell autonomous fashion. eIF6 acts by exerting translational control of adipogenic transcription factors like C/EBPß, C/EBPδ and ATF4 that have G/C rich or uORF sequences in their 5' UTR. The outcome of the translational activation by eIF6 is a reshaping of gene expression with increased levels of lipogenic and glycolytic enzymes. Finally, eIF6 levels modulate histone acetylation and amounts of rate-limiting fatty acid synthase (Fasn) mRNA. Since obesity, type 2 diabetes, and cancer require a Fasn-driven lipogenic state, we propose that eIF6 could be a therapeutic target for these diseases.


Assuntos
Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Fatores de Iniciação de Peptídeos/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/metabolismo , Transcrição Genética/genética , Células 3T3 , Acetilação , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Adipócitos/metabolismo , Adipogenia/genética , Animais , Western Blotting , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Eletroforese em Gel de Poliacrilamida , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Glicólise/genética , Células HEK293 , Hepatócitos/metabolismo , Código das Histonas , Humanos , Ácido Láctico/metabolismo , Lipogênese/genética , Fígado/diagnóstico por imagem , Fígado/metabolismo , Células-Tronco Mesenquimais , Camundongos , Oxirredução , Fatores de Iniciação de Peptídeos/metabolismo , Radiografia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Int J Cancer ; 136(5): E272-81, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25273595

RESUMO

Tumors characterized by an intense ribosome biogenesis often display a more aggressive behavior. Ribosomal RNA (rRNA) synthesis is controlled at several levels, including the epigenetic regulation of the condensation of chromatin portions containing rRNA genes. JHDM1B (Jumonji C histone demethylase 1B) is a histone demethylase able to regulate the accessibility of rRNA genes. In this study, we aimed to define the contribution of JHDM1B expression to the features of breast cancer, a tumor type whose behavior is related to the rate of ribosome biogenesis. We show that, in breast cancer-derived cell lines, the increase in rRNA transcription that follows JHDM1B knock-down is mirrored by an augmented cell proliferation only in p53 compromised cells, while p53 competent cells undergo cellular senescence and death. The latter effect appears to be mediated by a p38-dependent phosphorylation of p53, inducing the expression of p15(Ink4b) and p21(Waf1). In breast cancers, lower JHDM1B expression correlates with an increased size of specifically stained nucleolar organized regions, a morphological parameter directly related to the rate of ribosome biogenesis and with a poorer prognosis. In addition, in tumors lacking the controller function of p53, a lower expression of JHDM1B is associated with an increased tumor size at diagnosis. Altogether, our data indicate that epigenetic activation of rDNA genes induced by JHDM1B depletion is associated with a p53-dependent growth arrest, but may promote cancer cell growth when p53 is lacking.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Proteínas F-Box/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Ribossomos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Western Blotting , Neoplasias da Mama/mortalidade , Senescência Celular , Proteínas F-Box/antagonistas & inibidores , Proteínas F-Box/genética , Feminino , Humanos , Técnicas Imunoenzimáticas , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , RNA Mensageiro/genética , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética
11.
Biochim Biophys Acta ; 1849(7): 830-5, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25252159

RESUMO

Here we discuss the function of eukaryotic initiation factor 6 (eIF6; Tif6 in yeast). eIF6 binds 60S ribosomal subunits and blocks their joining to 40S. In this context, we propose that eIF6 impedes unproductive 80S formation, namely, the formation of 80S subunits without mRNA. Genetic evidence shows that eIF6 has a dual function: in yeast and mammals, nucleolar eIF6 is necessary for the biogenesis of 60S subunits. In mammals, cytoplasmic eIF6 is required for insulin and growth factor-stimulated translation. In contrast to other translation factors, eIF6 activity is not under mTOR control. The physiological significance of eIF6 impacts on cancer and on inherited Shwachman-Bodian-Diamond syndrome. eIF6 is overexpressed in specific human tumors. In a murine model of lymphomagenesis, eIF6 depletion leads to a striking increase of survival, without adverse effects. Shwachman-Bodian-Diamond syndrome is caused by loss of function of SBDS protein. In yeast, point mutations of Tif6, the yeast homolog of eIF6, rescue the quasi-lethal effect due to the loss of the SBDS homolog, Sdo1. We propose that eIF6 is a node regulator of ribosomal function and predict that prioritizing its pharmacological targeting will be of benefit in cancer and Shwachman-Bodian-Diamond syndrome. This article is part of a Special Issue entitled: Translation and Cancer.


Assuntos
Fatores de Iniciação em Eucariotos/metabolismo , Linfoma/metabolismo , Proteínas de Neoplasias/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Biossíntese de Proteínas , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Animais , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Fatores de Iniciação em Eucariotos/genética , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/metabolismo , Insuficiência Pancreática Exócrina/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipomatose/genética , Lipomatose/metabolismo , Lipomatose/patologia , Linfoma/genética , Linfoma/patologia , Camundongos , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fatores de Iniciação de Peptídeos/genética , Subunidades Ribossômicas Maiores de Eucariotos/genética , Síndrome de Shwachman-Diamond , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transativadores
12.
Cell Mol Life Sci ; 70(8): 1439-50, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23212600

RESUMO

The receptor for activated C-kinase 1 (RACK1) is a conserved structural protein of 40S ribosomes. Strikingly, deletion of RACK1 in yeast homolog Asc1 is not lethal. Mammalian RACK1 also interacts with many nonribosomal proteins, hinting at several extraribosomal functions. A knockout mouse for RACK1 has not previously been described. We produced the first RACK1 mutant mouse, in which both alleles of RACK1 gene are defective in RACK1 expression (ΔF/ΔF), in a pure C57 Black/6 background. In a sample of 287 pups, we observed no ΔF/ΔF mice (72 expected). Dissection and genotyping of embryos at various stages showed that lethality occurs at gastrulation. Heterozygotes (ΔF/+) have skin pigmentation defects with a white belly spot and hypopigmented tail and paws. ΔF/+ have a transient growth deficit (shown by measuring pup size at P11). The pigmentation deficit is partly reverted by p53 deletion, whereas the lethality is not. ΔF/+ livers have mild accumulation of inactive 80S ribosomal subunits by polysomal profile analysis. In ΔF/+ fibroblasts, protein synthesis response to extracellular and pharmacological stimuli is reduced. These results highlight the role of RACK1 as a ribosomal protein converging signaling to the translational apparatus.


Assuntos
Neuropeptídeos/genética , Pigmentação , Biossíntese de Proteínas , Animais , Células Cultivadas , Perda do Embrião/genética , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/ultraestrutura , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/metabolismo , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores de Quinase C Ativada , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
Cell Cycle ; 10(20): 3441-6, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22031223

RESUMO

Ribosome biogenesis and translation can be simplified as the processes of generating ribosomes and their use for decoding mRNA into a protein. Ribosome biogenesis has been efficiently studied in unicellular organisms like the budding yeast, allowing us a deep and basic knowledge of this process in growing cells. Translation has been modeled in vitro and in unicellular organisms. These studies have given us an important insight into the mechanisms and evolutionarily conserved aspects of ribosome biology. However, we advocate the need of the direct study of these processes in multicellular organisms. Analysis of ribosome biogenesis and translation in vivo in Metazoa and mammalian models is emerging and unveils the unexpected consequences of perturbed ribosome biogenesis and translation. Here, we will describe how one factor, eIF6, plays a crucial role both in the generation of the large ribosomal subunit and its availability for translation. From there, we will make specific conclusions on the physiological relevance of eIF6 in 80S formation, cell cycle progression and disease, raising the point that the control of gene expression may occur at the unexpected level of the large ribosomal subunit. In the future, the modulation of eIF6 binding to the 60S may be pharmacologically exploited to reduce the growth of cancer cells or ameliorate the phenotype of SDS syndrome.


Assuntos
Doenças da Medula Óssea/metabolismo , Ciclo Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Fatores de Iniciação em Eucariotos/metabolismo , Insuficiência Pancreática Exócrina/metabolismo , Regulação da Expressão Gênica/fisiologia , Lipomatose/metabolismo , Biossíntese de Proteínas/fisiologia , Subunidades Ribossômicas Maiores/fisiologia , Animais , Humanos , Modelos Biológicos , Subunidades Ribossômicas Maiores/metabolismo , Síndrome de Shwachman-Diamond , Transdução de Sinais/fisiologia
14.
Cancer Cell ; 19(6): 765-75, 2011 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-21665150

RESUMO

Eukaryotic Initiation Factor 6 (eIF6) controls translation by regulating 80S subunit formation. eIF6 is overexpressed in tumors. Here, we demonstrate that eIF6 inactivation delays tumorigenesis and reduces tumor growth in vivo. eIF6(+/-) mice resist to Myc-induced lymphomagenesis and have prolonged tumor-free survival and reduced tumor growth. eIF6(+/-) mice are also protected by p53 loss. Myc-driven lymphomas contain PKCßII and phosphorylated eIF6; eIF6 is phosphorylated by tumor-derived PKCßII, but not by the eIF4F activator mTORC1. Mutation of PKCßII phosphosite of eIF6 reduces tumor growth. Thus, eIF6 is a rate-limiting controller of initiation of translation, able to affect tumorigenesis and tumor growth. Modulation of eIF6 activity, independent from eIF4F complex, may lead to a therapeutical avenue in tumor therapy.


Assuntos
Transformação Celular Neoplásica/metabolismo , Linfoma/etiologia , Fatores de Iniciação de Peptídeos/fisiologia , Animais , Apoptose , Ciclo Celular , Citoplasma/metabolismo , Progressão da Doença , Genes myc , Linfoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Biossíntese de Proteínas , Proteína Quinase C/fisiologia , Proteína Quinase C beta , Proteína Supressora de Tumor p53/fisiologia
15.
PLoS One ; 6(12): e29136, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22216185

RESUMO

Initiation is the rate-limiting phase of protein synthesis, controlled by signaling pathways regulating the phosphorylation of translation factors. Initiation has three steps, 43S, 48S and 80S formation. 43S formation is repressed by eIF2α phosphorylation. The subsequent steps, 48S and 80S formation are enabled by growth factors. 48S relies on eIF4E-mediated assembly of eIF4F complex; 4E-BPs competitively displace eIF4E from eIF4F. Two pathways control eIF4F: 1) mTORc1 phosphorylates and inactivates 4E-BPs, leading to eIF4F formation; 2) the Ras-Mnk cascade phosphorylates eIF4E. We show that REN and NCI-H28 mesothelioma cells have constitutive activation of both pathways and maximal translation rate, in the absence of exogenous growth factors. Translation is rapidly abrogated by phosphorylation of eIF2α. Surprisingly, pharmacological inhibition of mTORc1 leads to the complete dephosphorylation of downstream targets, without changes in methionine incorporation. In addition, the combined administration of mTORc1 and MAPK/Mnk inhibitors has no additive effect. The inhibition of both mTORc1 and mTORc2 does not affect the metabolic rate. In spite of this, mTORc1 inhibition reduces eIF4F complex formation, and depresses translocation of TOP mRNAs on polysomes. Downregulation of eIF4E and overexpression of 4E-BP1 induce rapamycin sensitivity, suggesting that disruption of eIF4F complex, due to eIF4E modulation, competes with its recycling to ribosomes. These data suggest the existence of a dynamic equilibrium in which eIF4F is not essential for all mRNAs and is not displaced from translated mRNAs, before recycling to the next.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fator de Iniciação 4E em Eucariotos/metabolismo , Fosfoproteínas/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Humanos , Metionina/metabolismo , Fosforilação , Ligação Proteica , RNA Mensageiro/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Transcrição Genética
16.
Biochim Biophys Acta ; 1803(7): 826-31, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20359507

RESUMO

Adhesion to fibronectin stimulates protein synthesis (translation) of fibroblasts. Protein synthesis stimulation is dependent from the activation of beta(1)-integrin. beta(1)-Integrin elicits a PI3K cascade that modulates eIF4F (eukaryotic initiation factor 4F) complex formation. In the attempt to further dissect elements of the PI3K cascade that might be responsible for fibronectin-stimulated translation, we used pharmacological inhibitors of known kinases. We found that JNK inhibition, by SP600125 treatment, increased (35)S-methionine incorporation. Paradoxically, the increase in methionine incorporation was associated to a reduction of initiation of translation. These data imply that, during the adhesion of fibroblasts to fibronectin, conspicuous protein degradation occurs. Indeed, we found that inhibition of the proteasome by MG132 also increased methionine incorporation. Cotranslational degradation depended on PI3K activation. In spite of this, serum promoted translation, but not cotranslational degradation. The crosstalk between translation and degradation was further analyzed by studying the phosphorylation of initiation factors. Briefly, inhibition of JNK leads to eIF2alpha phosphorylation, which may account for the decrease in initiation of translation. In conclusion, beta(1)-integrin-activated translation causes the synthesis of short-lived proteins, whose degradation is controlled by the JNK pathway. We hypothesize that JNK is a general regulator of cotranslational degradation.


Assuntos
Adesão Celular/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Biossíntese de Proteínas , Animais , Antracenos/metabolismo , Linhagem Celular , Cromonas/metabolismo , Citoesqueleto/metabolismo , Inibidores Enzimáticos/metabolismo , Fibroblastos/citologia , Fibroblastos/fisiologia , Fibronectinas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Morfolinas/metabolismo , Células NIH 3T3 , Fosfatidilinositol 3-Quinases/metabolismo
17.
J Clin Psychopharmacol ; 29(6): 576-83, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19910724

RESUMO

The aim of this study was to model in mice the association between metabolic syndrome and the administration of atypical antipsychotic (AAP). Two dosages (4 and 8 mg/kg per day) of olanzapine (OL) were infused in 36 female mice for 30 days by osmotic mini-pumps. This study was also designed to further extend the implications raised in other experiments by our model of AAP-induced metabolic dysregulation. Through the use of the osmotic mini-pumps, this model is aimed to circumvent the shorter (than in humans) half-life of AAPs in rodents and to chronically administer OL by a reliable and less disturbing method. Indirect calorimetry was used to evaluate metabolic rate (MR) and respiratory exchange ratio together with weight and caloric intake. Serum insulin, leptin, and glucose tolerance (oral glucose tolerance test) were assessed. Pancreatic beta cells insulin levels, periuterine and liver fat content were also analyzed. Olanzapine-infused mice exhibited a reduction of overall MR (kilojoule per hour) and resting MR and respiratory exchange ratio, with periuterine fat significantly enlarged. All metabolic alterations were detected at the highest dose, with major effects found on weight gain and hyperphagia. Impaired glucose metabolism, associated with hyperinsulinemia and hyperleptinemia were found. Insulin resistance was evidenced by the raise of HOMA-IR index. Increased insulin and lipid storage were detected at pancreatic and hepatic levels respectively. These findings illustrate the development of a cluster of risk factors (metabolic syndrome) and, for the first time, a decrease of energy expenditure (MR) due to chronic OL infusion.


Assuntos
Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Dislipidemias/sangue , Metabolismo Energético/fisiologia , Intolerância à Glucose/sangue , Resistência à Insulina/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Dislipidemias/induzido quimicamente , Metabolismo Energético/efeitos dos fármacos , Feminino , Intolerância à Glucose/induzido quimicamente , Bombas de Infusão Implantáveis , Infusões Intravenosas , Síndrome Metabólica/sangue , Síndrome Metabólica/induzido quimicamente , Camundongos , Olanzapina , Fatores de Tempo
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