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MicroRNAs (miRNAs) have been demonstrated to modulate life span in the invertebrates C. elegans and Drosophila by targeting conserved pathways of aging, such as insulin/IGF-1 signaling (IIS). However, a role for miRNAs in modulating human longevity has not been fully explored. Here we investigated novel roles of miRNAs as a major epigenetic component of exceptional longevity in humans. By profiling the miRNAs in B-cells from Ashkenazi Jewish centenarians and 70-year-old controls without a longevity history, we found that the majority of differentially expressed miRNAs were upregulated in centenarians and predicted to modulate the IIS pathway. Notably, decreased IIS activity was found in B cells from centenarians who harbored these upregulated miRNAs. miR-142-3p, the top upregulated miRNA, was verified to dampen the IIS pathway by targeting multiple genes including GNB2, AKT1S1, RHEB and FURIN . Overexpression of miR-142-3p improved the stress resistance under genotoxicity and induced the impairment of cell cycle progression in IMR90 cells. Furthermore, mice injected with a miR-142-3p mimic showed reduced IIS signaling and improved longevity-associated phenotypes including enhanced stress resistance, improved diet/aging-induced glucose intolerance, and longevity-associated change of metabolic profile. These data suggest that miR-142-3p is involved in human longevity through regulating IIS-mediated pro-longevity effects. This study provides strong support for the use of miR-142-3p as a novel therapeutic to promote longevity or prevent aging/aging-related diseases in human.
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BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity. RESULTS: We employed massively parallel sequencing technology to identify miRNAs expressed in B-cells from Ashkenazi Jewish centenarians, i.e., those living to a hundred and a human model of exceptional longevity, and younger controls without a family history of longevity. With data from 26.7 million reads comprising 9.4 × 108 bp from 3 centenarian and 3 control individuals, we discovered a total of 276 known miRNAs and 8 unknown miRNAs ranging several orders of magnitude in expression levels, a typical characteristics of saturated miRNA-sequencing. A total of 22 miRNAs were found to be significantly upregulated, with only 2 miRNAs downregulated, in centenarians as compared to controls. Gene Ontology analysis of the predicted and validated targets of the 24 differentially expressed miRNAs indicated enrichment of functional pathways involved in cell metabolism, cell cycle, cell signaling, and cell differentiation. A cross sectional expression analysis of the differentially expressed miRNAs in B-cells from Ashkenazi Jewish individuals between the 50th and 100th years of age indicated that expression levels of miR-363* declined significantly with age. Centenarians, however, maintained the youthful expression level. This result suggests that miR-363* may be a candidate longevity-associated miRNA. CONCLUSION: Our comprehensive miRNA data provide a resource for further studies to identify genetic pathways associated with aging and longevity in humans.
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Linfócitos B/metabolismo , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , MicroRNAs/genética , Análise de Sequência de RNA , Idoso de 80 Anos ou mais , Envelhecimento/genética , Sequência de Bases , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate gene expression of their targets at the post-transcriptional levels. A single miRNA can target up to several hundred mRNAs, thus capable of significantly altering gene expression regulatory networks. In-depth study and characterization of miRNAs has elucidated their critical functions in development, homeostasis, and disease. A link between miRNAs and longevity has been demonstrated in C. elegans, implicating their role in regulation of lifespan and in the aging process. Recent years have witnessed unprecedented technological advances in studies of miRNAs, including ultra-high throughput sequencing technologies that allow comprehensive discovery of miRNAs and their targets. Here we review the latest experimental approaches from the perspective of understanding miRNA gene expression regulatory networks in aging. We provide a methodological work flow that can be employed to discover aging-related miRNAs and their targets, and to functionally validate their roles in aging. Finally, we review the links between miRNAs known to act in the conserved pathways of aging and major aging-related diseases. Taken together, we hope to provide a focused review to facilitate future endeavor of uncovering the functional role of miRNA in aging.
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In Pleurotus sp., green mold, which is considered a major epidemic, is caused by several Trichoderma species. To develop a rapid molecular marker specific for Trichoderma spp. that potentially cause green mold, eleven Trichoderma species were collected from mushroom farms and the Korean Agricultural Culture Collection (KACC). A dominant fungal isolate from a green mold-infected substrate was identified as Trichoderma pleuroticola based on the sequences of its internal transcribed spacer (ITS) and translation elongation factor 1-α (tef1) genes. In artificial inoculation tests, all Trichoderma spp., including T. atroviride, T. cf. virens, T. citrinoviride, T. harzianum, T. koningii, T. longibrachiatum, T. pleurotum, and T. pleuroticola, showed pathogenicity to some extent, and the observed symptoms were soaked mycelia with a red-brown pigment and retarded mycelium regeneration. A molecular marker was developed for the rapid detection of wide range of Trichoderma spp. based on the DNA sequence alignment of the ITS1 and ITS2 regions of Trichoderma spp. The developed primer set detected only Trichoderma spp., and no cross reactivity with edible mushrooms was observed. The detection limits for the PCR assay of T. harzianum (KACC40558), T. pleurotum (KACC44537), and T. pleuroticola (CAF-TP3) were found to be 500, 50, and 5 fg, respectively, and the detection limit for the pathogen-to-host ratio was approximately 1:10,000 (wt/wt).
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Skeletal muscle is one of the major organs responsible for body movements and metabolism making up approximately 40% of the total body mass. During aging, skeletal muscle exhibits a degenerative age-associated decline in mass and function termed sarcopenia. This age-associated dysfunction of skeletal muscle is a major criterion of morbidity, mortality, and overall declines of quality of life in the elderly people. Therefore, researchers have focused on identifying modulators of muscle aging process including messenger RNAs, proteins, and recently small noncoding RNAs such as microRNAs (miRNAs). In particular, miRNAs have been demonstrated to play a critical role in skeletal muscle development and homeostasis. Recent studies revealed that miRNAs were also involved in muscle aging processes and the rejuvenation of aged muscle by regulating important molecules and pathways of aging including insulin-like growth factors, nicotine-adenine dinucleotide (+)-dependent protein deacetylase sirtuin-1, telomerase reverse transcriptase, and transforming growth factor-ß signaling pathway. Over the years, miRNAs have emerged as promising candidates for biomarkers of sarcopenia and targets for interventions to slow muscle aging. Here, we comprehensively review the current knowledge on the role of miRNAs in skeletal muscle aging and highlight their potential as biomarkers or therapeutic targets for skeletal muscle health.
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Senescência Celular/genética , MicroRNAs/genética , Músculo Esquelético/metabolismo , Sarcopenia/genética , Animais , Marcadores Genéticos , HumanosRESUMO
Human aging is a lifelong process characterized by a continuous trade-off between pro-and anti-inflammatory responses, where the best-adapted and/or remodeled genetic/epigenetic profile may develop a longevity phenotype. Centenarians and their offspring represent such a phenotype and their comparison to patients with age-related diseases (ARDs) is expected to maximize the chance to unravel the genetic makeup that better associates with healthy aging trajectories. Seemingly, such comparison is expected to allow the discovery of new biomarkers of longevity together with risk factor for the most common ARDs. MicroRNAs (miRNAs) and their shuttles (extracellular vesicles in particular) are currently conceived as those endowed with the strongest ability to provide information about the trajectories of healthy and unhealthy aging. We review the available data on miRNAs in aging and underpin the evidence suggesting that circulating miRNAs (and cognate shuttles), especially those involved in the regulation of inflammation (inflamma-miRs) may constitute biomarkers capable of reliably depicting healthy and unhealthy aging trajectories.
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Envelhecimento/sangue , Vesículas Extracelulares/metabolismo , MicroRNAs/sangue , Envelhecimento/genética , Envelhecimento/patologia , Animais , Biomarcadores/sangue , Vesículas Extracelulares/genética , Humanos , Inflamação/sangue , Inflamação/genética , MicroRNAs/genéticaRESUMO
Age-associated loss of muscle mass and function is a major cause of morbidity and mortality in the elderly adults. Muscular atrophy can also be induced by disuse associated with long-term bed rest or disease. Although miRNAs regulate muscle growth, regeneration, and aging, their potential role in acute muscle atrophy is poorly understood. Furthermore, alterations in circulating miRNA levels have been shown to occur during aging but their potential as noninvasive biomarkers for muscle atrophy remains largely unexplored. Here, we report comprehensive miRNA expression profiles by miRNA-seq analysis in tibialis anterior muscle and serum of a disuse-induced atrophy mouse model, mimicking the acute atrophy following long-term bed rest, as compared to those of young and old mice. Comparative analysis and validation studies have revealed that miR-455-3p was significantly decreased in muscle of both induced-atrophy model and old mice, whereas miR-434-3p was decreased in both serum and muscle of old mice, as compared to young mice. Furthermore, upregulation of miR-455-3p in fully differentiated C2C12 myoblasts induced a hypertrophic phenotype. These results suggest that deregulation of miR-455-3p may play a functional role in muscle atrophy and miR-434-3p could be a candidate serum biomarker of muscle aging.
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Envelhecimento/genética , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , RNA/genética , Regulação para Cima , Envelhecimento/metabolismo , Animais , Biomarcadores/metabolismo , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
There is a need to develop a colorectal cancer (CRC) screening test that is noninvasive, cost effective, and sensitive enough to detect preneoplastic lesions. This case-control study examined the feasibility of using circulating extracellular microRNAs (miRNAs) to differentiate a spectrum of colorectal neoplasia of various severity and hence for early detection of colorectal neoplasia. Archived serum samples of 10 normal controls and 31 cases, including 10 with nonadvanced adenoma, 10 with advanced adenoma, and 11 with CRC, were profiled for circulating miRNAs using next-generation sequencing. Multiple linear regression, adjusting for age, gender, and smoking status, compared controls and the 3 case groups for levels of 175 miRNAs that met stringent criteria for miRNA sequencing analysis. Of the 175 miRNAs, 106 miRNAs were downregulated according to severity of neoplasia and showed a relative decrease in the expression from controls to nonadvanced adenoma to advanced adenoma to CRC (Ptrend < 0.05). Pairwise group comparisons showed that 39 and 80 miRNAs were differentially expressed in the advanced adenoma and CRC groups compared with the controls, respectively. Differences in miRNA levels between the nonadvanced adenoma group and controls were modest. Our study found that expression of many miRNAs in serum was inversely correlated with the severity of colorectal neoplasia, and differential miRNA profiles were apparent in preneoplastic cases with advanced lesions, suggesting circulating miRNAs could serve as potential biomarkers for CRC screening.
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Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/sangue , MicroRNAs/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Soro/metabolismoRESUMO
Zmpste24 is a metalloproteinase responsible for the posttranslational processing and cleavage of prelamin A into mature laminA. Zmpste24(-/-) mice display a range of progeroid phenotypes overlapping with mice expressing progerin, an altered version of lamin A associated with Hutchinson-Gilford progeria syndrome (HGPS). Increasing evidence has demonstrated that miRNAs contribute to the regulation of normal aging process, but their roles in progeroid disorders remain poorly understood. Here we report the miRNA transcriptomes of mouse embryonic fibroblasts (MEFs) established from wild type (WT) and Zmpste24(-/-) progeroid mice using a massively parallel sequencing technology. With data from 19.5 × 10(6) reads from WT MEFs and 16.5 × 10(6) reads from Zmpste24(-/-) MEFs, we discovered a total of 306 known miRNAs expressed in MEFs with a wide dynamic range of read counts ranging from 10 to over 1 million. A total of 8 miRNAs were found to be significantly down-regulated, with only 2 miRNAs upregulated, in Zmpste24(-/-) MEFs as compared to WT MEFs. Functional studies revealed that miR-365, a significantly down-regulated miRNA in Zmpste24(-/-) MEFs, modulates cellular growth phenotypes in MEFs. Overexpression of miR-365 in Zmpste24(-/-) MEFs increased cellular proliferation and decreased the percentage of SA-ß-gal-positive cells, while inhibition of miR-365 function led to an increase of SA-ß-gal-positive cells in WT MEFs. Furthermore, we identified Rasd1, a member of the Ras superfamily of small GTPases, as a functional target of miR-365. While expression of miR-365 suppressed Rasd1 3' UTR luciferase-reporter activity, this effect was lost with mutations in the putative 3' UTR target-site. Consistently, expression levels of miR-365 were found to inversely correlate with endogenous Rasd1 levels. These findings suggest that miR-365 is down-regulated in Zmpste24(-/-) MEFs and acts as a novel negative regulator of Rasd1. Our comprehensive miRNA data provide a resource to study gene regulatory networks in MEFs.
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Proliferação de Células/genética , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Proteínas de Membrana/metabolismo , Metaloendopeptidases/metabolismo , MicroRNAs/metabolismo , Sequência de Aminoácidos , Animais , Senescência Celular/genética , Regulação para Baixo , Fibroblastos/citologia , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Membrana/genética , Metaloendopeptidases/genética , Camundongos , Camundongos Knockout , MicroRNAs/genética , Dados de Sequência Molecular , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
The p53 tumor suppressor has long been envisaged to preserve genetic stability by the induction of cell cycle checkpoints and apoptosis. More recently, p53 has been implicated to play roles in DNA repair responses to genotoxic stresses. UV-damage and the damage caused by certain chemotherapeutics including cisplatin and nitrogen mustards are known to be repaired by the nucleotide excision repair (NER) pathway which is reportedly regulated by p53 and its downstream genes. There are evidences to suggest that the base excision repair (BER) induced by the base-damaging agent methyl methanesulfonate (MMS) is partially deficient in cells lacking functional p53. This result suggests that the activity of BER might be also dependent on the p53 status. In this review, we discuss the possibilities that p53 regulates BER as well as NER; these are one of the most significant potentials of p53 tumor suppressor for repairing the vast majority of DNA damages that is incurred from various environmental stresses.
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Dano ao DNA , Reparo do DNA/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Humanos , CamundongosRESUMO
Four guaia-12,6-olide type sesquiterpene lactones, aguerin B (1), 8alpha-acetoxyzaluzanin C (2), cynaropicrin (3), and deacylcynaropicrin (4), were isolated from the flowers of Hemisteptia lyrata Bunge. It is the first report on the isolation of compounds 1-4 from Hemisteptia species. All the isolates (1-4) were examined for their cytotoxic activity against SK-OV-3, LOX-IMVI, A549, MCF-7, PC-3, and HCT-15 human cancer cell lines.
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Antineoplásicos/toxicidade , Asteraceae , Flores/toxicidade , Lactonas/toxicidade , Sesquiterpenos/toxicidade , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificaçãoRESUMO
A polysaccharide fraction, AIP1, purified from Artemisia iwayomogi was shown to have immunomodulating and anti-tumor activities in mice. In order to determine how the AIP1 fraction exhibits the immunomodulating activity, the effect of the fraction on the apoptosis of mouse spleen cells was investigated. Treatment of the mouse spleen cells with the AIP1 fraction resulted in the suppression of apoptotic death and an extension of cell survival in culture, indicating that the fraction might modulate the death of spleen cells. Treatment of the mice with the AIP1 fraction in vivo also resulted in less apoptosis of the spleen cells, which indicates the physiological relevance of the anti-apoptosis effect of the fraction in vitro. A mouse gene array was used to determine the profile of the gene expression change showing a pattern of up- and down-regulated genes by the AIP1 treatment. This study provides preliminary information regarding the immunomodulatory mechanism of the AIP1 fraction.
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Apoptose/efeitos dos fármacos , Apoptose/genética , Células Cultivadas/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Polissacarídeos/genética , Polissacarídeos/farmacologia , Baço/citologia , Baço/efeitos dos fármacos , Animais , Artemisia , Células da Medula Óssea/efeitos dos fármacos , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Extratos Vegetais , Folhas de Planta , Polissacarídeos/imunologiaRESUMO
The insulin-like growth factor 1 (IGF-1) signaling pathway regulates critical biological processes including development, homeostasis, and aging. Dysregulation of this pathway has been implicated in a myriad of diseases such as cancers, neurodegenerative diseases, and metabolic disorders, making the IGF-1 signaling pathway a prime target to develop therapeutic and intervention strategies. Recently, small non-coding RNA molecules in â¼22 nucleotide length, microRNAs (miRNAs), have emerged as a new regulator of biological processes in virtually all organ systems and increasing studies are linking altered miRNA function to disease mechanisms. A miRNA binds to 3'UTRs of multiple target genes and coordinately downregulates their expression, thereby exerting a profound influence on gene regulatory networks. Here we review the components of the IGF-1 signaling pathway that are known targets of miRNA regulation, and highlight recent studies that suggest therapeutic potential of these miRNAs against various diseases.
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MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. They are involved in important biological processes including development, homeostasis, and ageing. Recently, extracellular miRNAs have been discovered in the bloodstream and bodily fluids. These miRNAs are shown to be secreted and circulating in microvesicles (MVs), or in complex with other factors such as RNA-binding proteins and high-density lipoprotein (HDL) particles. These cell-free, circulating miRNAs can be taken into and function as negative regulators of target genes in recipient cells. Here we review the biogenesis and uptake of circulating miRNAs as well as their profiles in ageing and ageing-related diseases. We discuss the emerging role of circulating miRNAs as biomarkers and therapeutic targets.
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Envelhecimento/genética , Doença/genética , MicroRNAs/sangue , MicroRNAs/genética , Envelhecimento/metabolismo , Animais , Transporte Biológico , Biomarcadores/sangue , Biomarcadores/metabolismo , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo , MicroRNAs/uso terapêuticoRESUMO
AIM: p53 is reportedly activated without any genotoxicity through redox modulation of redox factor 1 (REF1). REF1 is documented to modulate the redox status under selenomethionine (SeMet). In this study, we investigated the mechanism of p53 stabilization by SeMet. MATERIALS AND METHODS: We mainly used ubiquitination assay and immunoprecipitation to determine the potential role of REF1 and c-jun N-terminal kinase 1 (JNK) in modulation of p53 stabilization by SeMet. RESULTS: The amount of ubiquitinated p53 decreased significantly under SeMet treatment, suggesting that SeMet might inhibit the proteasome-dependent degradation of p53. In addition, we observed that JNK was considerably associated with p53 in REF1 siRNA-treated cells, implying a possible role for SeMet-induced REF1 activity in modulation of the interaction between JNK and p53 via changes in p53 redox status. CONCLUSION: Our results suggest that the alternate mechanism of p53 stabilization by SeMet might provide an important clue in elucidating the molecular mechanism of chemopreventative compounds against various oxidative stresses.
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DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Selenometionina/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Humanos , Espécies Reativas de Oxigênio/metabolismo , UbiquitinaçãoRESUMO
Organic selenium compounds have been documented to play a role in cancer prevention. Our previous study showed that selenomethionine (SeMet) induces p53 activation without genotoxic effects including apoptosis and cell cycle arrest. In this study, we investigated the mechanism by which organic selenium compounds promote p53-mediated base excision repair (BER) activity. Our data demonstrated for the first time that the interaction between growth arrest and DNA damage-inducible protein 45A (Gadd45a), which is a p53-activated downstream gene, and two BER-mediated repair proteins, proliferating cell nuclear antigen (PCNA) and apurinic/apyrimidinic endonuclease (APE1/Ref-1), was significantly increased in a p53-dependent manner following treatment with organic selenium compounds. Furthermore, we observed that the activity of APE1 was significantly increased in a p53-dependent manner in response to the organic selenium compounds. These results suggest that BER activity is dependent on wild-type p53 activity and is mediated by the modulation of protein interactions between Gadd45a and repair proteins in response to organic selenium compounds. We propose that p53-dependent BER activity is a distinct chemopreventive mechanism mediated by organic selenium compounds, and that this may provide insight into the development of effective chemopreventive strategies against various oxidative stresses that contribute to a variety of human diseases, particularly cancer.
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Proteínas de Ciclo Celular/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas Nucleares/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Selenometionina/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Quimioprevenção , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Dano ao DNA , Reparo do DNA/genética , Ativação Enzimática/efeitos dos fármacos , Humanos , Complexos Multiproteicos/metabolismo , Estresse Oxidativo/genética , Interferência de RNA , RNA Interferente Pequeno , Proteína Supressora de Tumor p53/genéticaRESUMO
Recently, mild hyperthermia was shown to induce cell cycle arrest at the G2/M phase transition without leading to DNA damage. The mechanism of this regulation has not yet been elucidated, although p53 has been shown to be activated in response to mild hyperthermia. Here, we report the role of thioredoxin (TXN) in mild hyperthermia-induced cellular responses. Our data showed that the protein levels of p53 and its downstream gene, Gadd45a, which is an indicator of G2/M arrest, were significantly decreased in TXN siRNA-treated cells under conditions of mild hyperthermia (41ËC, 60 min) as compared to TXN wild-type cells, implying that TXN might play an important role in mild hyperthermia-induced G2/M arrest via p53 and Gadd45a activation. Furthermore, the release of cyclin-dependent kinase Cdc2, known to be regulated by Gadd45a under G2/M arrest, was inhibited from the nucleus for arrest in the G2/M phase in TXN downregulated cells under mild hyperthermia. We suggest that G2/M arrest mediated via the TXN-modulated p53 in response to mild hyperthermia may provide critical insight into the clinical use of mild hyperthermia to induce an adaptive response against genotoxic stresses.
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Hipertermia Induzida , Tiorredoxinas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Quinase CDC2 , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Divisão Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Ciclina B/genética , Ciclina B/metabolismo , Quinases Ciclina-Dependentes , Dano ao DNA/genética , Regulação para Baixo , Fase G2/genética , Humanos , Mitose/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oxirredução , Tiorredoxinas/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
The element selenium (Se) was identified, nearly 40 years ago, as being essential in the nutrition of animals and humans. In addition, antitumorigenic effects of Se compounds have been described in a variety of in vitro and animal models, suggesting that supplemental Se in human diets may reduce cancer risk. Apparent mechanisms underlying the potential of Se compounds as cancer chemopreventive agents have been suggested. Some recent clinical trials, however, have shed doubt on the anticancer effects of Se. The contradictory findings and consequent controversy might be due to the lack of understanding of the mechanisms underlying Se biology. This article reviews current knowledge on this topic and addresses the disparate viewpoints on the chemopreventive effects of Se, the human populations.
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Quimioprevenção/métodos , Neoplasias/prevenção & controle , Selênio/uso terapêutico , Animais , HumanosRESUMO
Selenomethionine (SeMet) has been identified as a chemopreventive antioxidant to activate p53-mediated nucleotide excision repair. In this study, we examined whether p53-mediated base excision repair (BER) might be induced by SeMet. When methyl methanesulfonate, a BER-inducing agent, was treated in the cells, DNA damage was rapidly decreased in the presence of SeMet. In addition, our data showed that the removal of apurinic/apyrimidinic sites was significantly enhanced in the presence of SeMet. Furthermore, we observed that the expression of gadd45a, known to involve BER as one of the p53 downstream genes, was increased by SeMet in p53 wild-type RKO cells. Those results supported the proposal that BER activity might be dependent on wild-type p53 under the modulation of gadd45a expression in response to SeMet. We suggested that p53-dependent BER activity as a distinct mechanism of SeMet might play an important role to prevent cancer caused by various oxidative stresses.
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Antioxidantes/farmacologia , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Selenometionina/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Dano ao DNA/genética , Reparo do DNA/genética , Expressão Gênica , Humanos , Metanossulfonato de Metila/efeitos adversos , Mutação , Proteínas Nucleares/genética , RNA Interferente Pequeno , Transfecção , Proteína Supressora de Tumor p53/genéticaRESUMO
Wnt signaling is implicated in a variety of developmental and pathological processes. The molecular mechanisms governing the secretion of Wnt ligands remain to be elucidated. Wntless, an evolutionarily conserved multipass transmembrane protein, is a dedicated secretion factor of Wnt proteins that participates in Drosophila melanogaster embryogenesis. In this study, we show that Xenopus laevis Wntless (XWntless) regulates the secretion of a specific Wnt ligand, XWnt4, and that this regulation is specifically required for eye development in Xenopus. Moreover, the Retromer complex is required for XWntless recycling to regulate the XWnt4-mediated eye development. Inhibition of Retromer function by Vps35 morpholino (MO) resulted in various Wnt deficiency phenotypes, affecting mesoderm induction, gastrulation cell movements, neural induction, neural tube closure, and eye development. Overexpression of XWntless led to the rescue of Vps35 MO-mediated eye defects but not other deficiencies. These results collectively suggest that XWntless and the Retromer complex are required for the efficient secretion of XWnt4, facilitating its role in Xenopus eye development.