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1.
Occup Environ Med ; 80(6): 304-311, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37116959

RESUMO

OBJECTIVES: This study aimed to examine the prospective association among objectively measured average working hours (AWHs), frequency of long working hours (FLWHs; defined as ≥205 working hours/month (≥45 hours/week)) for 6 months, and workers' self-reported psychological and physical health. METHODS: The study included 15 143 workers from 5 Japanese companies. We collected monthly attendance records over 6 months before distributing a questionnaire survey on psychological/physical stress responses and work-related demographics. We then evaluated the associations of those attendance records with psychological/physical measures using analysis of covariance adjusted for sex, age, employment, job type, working conditions, work site and experience of emergency state due to COVID-19. RESULTS: Irritability, anxiety and depression were significantly greater at ≥180 hours (≥45 hours/week), and fatigue and lack of vigour were greater at ≥205 hours than those of the normal working-hour group (140-180 hours/month [35-45 hours/week]). Psychological indices increased significantly with FLWH, with ≥3 times for irritability, depression and fatigue; ≥2 times for lack of vigour; and ≥1 time for anxiety when compared with no long working hours. No significant associations were observed between AWH or FLWH and physical stress responses. CONCLUSIONS: Longer AWH was associated with higher levels of psychological stress responses. The effects of FLWH in the past 6 months varied among the psychological stress responses and did not occur for physical complaints. Under circumstances requiring long hours, workers' mental health should be protected through minimising the frequency of long work hours.


Assuntos
COVID-19 , Humanos , Estudos de Coortes , COVID-19/epidemiologia , Emprego , Fadiga/epidemiologia , Inquéritos e Questionários , Estresse Psicológico/psicologia
2.
Int Arch Occup Environ Health ; 95(3): 685-699, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34669025

RESUMO

PURPOSE: We aimed to examine the prospective associations of monthly working hours measured in a month, the 6-month averaged hours, and the frequency of long working hours (≥ 205 h/month) during the past 6 months with health indicators. METHODS: This study included 6,806 Japanese company workers (response rate = 86.6%). Data on the workers' monthly attendance during the second half of fiscal year 2016 and annual health checkups in fiscal years 2016 and 2017 were collected. We evaluated the association of the above three types of monthly working hours with subsequent health checkup data in fiscal year 2017. We adjusted for the corresponding data in fiscal year 2016. RESULTS: Multivariate logistic regression analyses revealed significant associations between monthly working hours and workers' systolic and diastolic blood pressure as well as aspartate aminotransferase, alanine aminotransferase, low-density lipoprotein cholesterol (LDL), and triglyceride levels. However, the associations were not consistent between months. The average monthly working hours were significantly associated with higher LDL levels for the 220-240 h/mo group (OR: 1.49, 95%CI: 1.07-2.08) and lower triglyceride levels for the < 140 h/mo group (OR: 0.15, 95%CI: 0.03-0.77), compared to the 140-180 h/mo group. The frequency of long working hours was significantly associated with higher LDL levels. CONCLUSIONS: Working hours over several months produced various associations with health indicators compared to those measured in a single month. Our present data suggest that the effects of average or frequency of long working hours during the past 6 months are likely to appear in LDL levels.


Assuntos
Saúde Ocupacional , Estudos de Coortes , Humanos , Japão/epidemiologia
3.
Ind Health ; 60(4): 395-404, 2022 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-34719602

RESUMO

How work burden affects physical and mental health has already been studied extensively; however, many issues have remained unexamined. In 2017, we commenced a prospective cohort study of workers at companies in Japan, with a follow-up period of 5-10 years, in order to investigate the current situation of overwork-related health outcomes. From 2017 to 2020, a target population of 150,000 workers across 8 companies was identified. Of these, almost 40,000 workers agreed to participate in the baseline survey. Data on working hours, medical check-up measurements, occupational stress levels, and lifestyle habits were collected. The average age of the participants at baseline was 39.2 ± 11.7 years; 73.1% were men, and 87.7% were regular employees. The most common working hours by self-reported was 41-50 hours per week during normal season, and it increased to more than 50 hours during busy season. Furthermore, more than half of the participants reportedly experienced a form of sleep problem, and the percentage of those who experienced nonrestorative sleep was particularly high.


Assuntos
Saúde Ocupacional , Estresse Ocupacional , Adulto , Estudos de Coortes , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
4.
Ind Health ; 58(5): 487, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33028794

RESUMO

Table 3 of the above paper appeared incorrectly in print. Percentage figures on the table were inadvertently listed as negative values. These errors were corrected in online versions of this paper, as shown below.

5.
Ind Health ; 58(3): 265-275, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-31685757

RESUMO

This study investigated the correlation between objective and subjective working hours (OWH and SWH, respectively) and their relation to the workers' health. The study included 6,806 workers of a Japanese company (response rate=86.6%). OWH were collected as the monthly data during fiscal year 2017 from the company record. SWH were self-reported as the weekly data during the past month in November 2017. Both OWH and SWH corresponded to the same period of one month (October 2017). Additionally, the data for the annual health checkup in fiscal year 2017 and self-reported mental health in November 2017 were collected. The results indicated that the longer OWH was related to more underestimation of SWH. The analyses of covariance adjusted for the selected variables showed that irrespective of OWH or SWH, significant relationships were found for stress responses but not for body mass index, aspartate and alanine aminotransferase, fasting blood glucose, hemoglobin A1c, high-density lipoprotein cholesterol, or triglyceride. However, significant relationships with only OWH were noted for systolic and diastolic blood pressure, low-density lipoprotein cholesterol, gamma-glutamyl transpeptidase, and positive work-related state of mind. The present findings show that SWH should be used carefully when assessing the health effects of long working hours.


Assuntos
Saúde Ocupacional , Autorrelato , Carga de Trabalho/psicologia , Adulto , Índice de Massa Corporal , Feminino , Nível de Saúde , Humanos , Japão , Masculino , Saúde Mental , Pessoa de Meia-Idade , Estresse Ocupacional , Admissão e Escalonamento de Pessoal
7.
PLoS One ; 10(11): e0142779, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26558900

RESUMO

OBJECTIVE: Risk models and scores have been developed to predict incidence of type 2 diabetes in Western populations, but their performance may differ when applied to non-Western populations. We developed and validated a risk score for predicting 3-year incidence of type 2 diabetes in a Japanese population. METHODS: Participants were 37,416 men and women, aged 30 or older, who received periodic health checkup in 2008-2009 in eight companies. Diabetes was defined as fasting plasma glucose (FPG) ≥ 126 mg/dl, random plasma glucose ≥ 200 mg/dl, glycated hemoglobin (HbA1c) ≥ 6.5%, or receiving medical treatment for diabetes. Risk scores on non-invasive and invasive models including FPG and HbA1c were developed using logistic regression in a derivation cohort and validated in the remaining cohort. RESULTS: The area under the curve (AUC) for the non-invasive model including age, sex, body mass index, waist circumference, hypertension, and smoking status was 0.717 (95% CI, 0.703-0.731). In the invasive model in which both FPG and HbA1c were added to the non-invasive model, AUC was increased to 0.893 (95% CI, 0.883-0.902). When the risk scores were applied to the validation cohort, AUCs (95% CI) for the non-invasive and invasive model were 0.734 (0.715-0.753) and 0.882 (0.868-0.895), respectively. Participants with a non-invasive score of ≥ 15 and invasive score of ≥ 19 were projected to have >20% and >50% risk, respectively, of developing type 2 diabetes within 3 years. CONCLUSIONS: The simple risk score of the non-invasive model might be useful for predicting incident type 2 diabetes, and its predictive performance may be markedly improved by incorporating FPG and HbA1c.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Inquéritos Epidemiológicos , Saúde Ocupacional , Adulto , Área Sob a Curva , Glicemia/análise , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Incidência , Japão/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Curva ROC , Fatores de Risco , Fumar , Circunferência da Cintura
9.
PLoS One ; 10(7): e0132166, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26200457

RESUMO

AIMS: To examine the association of smoking status, smoking intensity, and smoking cessation with the risk of type 2 diabetes (T2D) using a large database. METHODS: The present study included 53,930 Japanese employees, aged 15 to 83 years, who received health check-up and did not have diabetes at baseline. Diabetes was defined as fasting plasma glucose ≥126 mg/dl, random plasma glucose ≥200 mg/dl, HbA1c ≥6.5% (≥48 mmol/mol), or receiving medication for diabetes. Cox proportional-hazards regression models were used to investigate the association between smoking and the risk of diabetes. RESULTS: During 3.9 years of median follow-up, 2,441 (4.5%) individuals developed T2D. The multivariable-adjusted hazard ratios (95% CI) for diabetes were 1 (reference), 1.16 (1.04 to 1.30) and 1.34 (1.22 to 1.48) for never smokers, former smokers, and current smokers, respectively. Diabetes risk increased with increasing numbers of cigarette consumption among current smokers (P for trend <0.001). Although the relative risk of diabetes was greater among subjects with lower BMIs (< 23 kg/m2), attributable risk was greater in subjects with higher BMIs (≥ 23 kg/m2). Compared with individuals who had never smoked, former smokers who quit less than 5 years, 5 to 9 years, and 10 years or more exhibited hazards ratios for diabetes of 1.36 (1.14 to 1.62), 1.23 (1.01 to 1.51), and 1.02 (0.85 to 1.23), respectively. CONCLUSIONS: Results suggest that cigarette smoking is associated with an increased risk of T2D, which may decrease to the level of a never smoker after 10 years of smoking cessation.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Fumar/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Abandono do Hábito de Fumar/métodos , Adulto Jovem
10.
J Biol Chem ; 290(14): 8904-12, 2015 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-25670865

RESUMO

Downstream signaling of physiological and pathological cell responses depends on post-translational modification such as ubiquitination. The mechanisms regulating downstream DNA damage response (DDR) signaling are not completely elucidated. Sirtuin 1 (SIRT1), the founding member of Class III histone deacetylases, regulates multiple steps in DDR and is closely associated with many physiological and pathological processes. However, the role of post-translational modification or ubiquitination of SIRT1 during DDR is unclear. We show that SIRT1 is dynamically and distinctly ubiquitinated in response to DNA damage. SIRT1 was ubiquitinated by the MDM2 E3 ligase in vitro and in vivo. SIRT1 ubiquitination under normal conditions had no effect on its enzymatic activity or rate of degradation; hypo-ubiquitination, however, reduced SIRT1 nuclear localization. Ubiquitination of SIRT1 affected its function in cell death and survival in response to DNA damage. Our results suggest that ubiquitination is required for SIRT1 function during DDR.


Assuntos
Morte Celular/fisiologia , Sobrevivência Celular/fisiologia , Dano ao DNA , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Sirtuína 1/fisiologia , Sequência de Bases , Western Blotting , Linhagem Celular , Primers do DNA , Imunofluorescência , Humanos , Sirtuína 1/metabolismo , Ubiquitinação
11.
Cell Cycle ; 14(4): 544-53, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25590559

RESUMO

The presence of more than 2 centrosomes (centrosome amplification) leads to defective mitosis and chromosome segregation errors, is frequently found in a variety of cancer types, and believed to be the major cause of chromosome instability. One mechanism for generation of amplified centrosomes is over-duplication of centrosomes in a single cell cycle, which is expected to occur when cells are temporarily arrested. There are a growing number of kinases that are critical for induction and promotion of centrosome amplification in the cell cycle-arrested cells, including Rho-associated kinase (ROCK2), Polo-like kinase 2 (PLK2) and PLK4. Here, we tested whether these kinases induce centrosome amplification in a linear pathway or parallel pathways. We first confirmed that ROCK2, PLK2 and PLK4 are all essential for centrosomes to re-duplicate in the cells arrested by exposure to DNA synthesis inhibitor. Using the centrosome amplification rescue assay, we found that PLK2 indirectly activates ROCK2 via phosphorylating nucleophosmin (NPM), and PLK4 functions downstream of ROCK2 to drive centrosome amplification in the arrested cells.


Assuntos
Centrossomo/fisiologia , Mitose/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinases Associadas a rho/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Técnicas de Inativação de Genes , Immunoblotting , Proteínas Nucleares/metabolismo , Nucleofosmina , Fosforilação , RNA Interferente Pequeno/genética , Proteína Supressora de Tumor p53/genética
12.
Circ J ; 78(5): 1160-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24662439

RESUMO

BACKGROUND: Waist-to-height ratio (WHtR) has been suggested as a better screening tool than body mass index (BMI) and waist circumference (WC) for assessing cardiometabolic risk. However, most previous studies did not consider age. METHODS AND RESULTS: Participants were 45,618 men and 8,092 women aged 15-84 years who received periodic health checkups in 9 companies in Japan. Clustering of cardiometabolic risk factors was defined by the existence of 2 or more of high blood pressure, hyperglycemia, and dyslipidemia. In both men and women, unadjusted area under the curve (AUC) of the receiver-operating characteristic curve for WHtR in detecting the clustering of cardiometabolic risk factors was significantly higher than that for either BMI or WC; the AUCs for WHtR, BMI, and WC, respectively, were 0.734, 0.705, and 0.717 in men and 0.782, 0.762, and 0.755 in women. After adjustment for age, however, such differences were not observed; the corresponding values were 0.702, 0.701, and 0.696 in men. In women, the age-adjusted AUC for BMI was slightly higher than for other indices (WHtR, 0.721; BMI, 0.726; WC, 0.707). CONCLUSIONS: The screening performance of WHtR for detecting the clustering cardiometabolic risk factors was not superior to that of BMI.


Assuntos
Índice de Massa Corporal , Dislipidemias , Hiperglicemia , Hipertensão , Circunferência da Cintura , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Dislipidemias/epidemiologia , Dislipidemias/patologia , Dislipidemias/fisiopatologia , Feminino , Humanos , Hiperglicemia/epidemiologia , Hiperglicemia/patologia , Hiperglicemia/fisiopatologia , Hipertensão/epidemiologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
13.
Cell Cycle ; 11(20): 3779-91, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23022877

RESUMO

Centrosome duplication is controlled both negatively and positively by a number of proteins. The activities and stabilities of those regulatory proteins are in many cases controlled by posttranslational modifications. Although acetylation and deacetylation are highly common posttranslational modifications, their roles in the regulation of centrosome duplication had not been closely examined. Here, through focusing on the deacetylases, we investigated the role of acetylation/deacetylation in the regulation of centrosome duplication and induction of abnormal amplification of centrosomes. We found that the deacetylation event negatively controls centrosome duplication and amplification. Of the 18 total known deacetylases (HDAC1-11, SIRT1-7), ten deacetylases possess the activity to suppress centrosome amplification, and their centrosome amplification suppressing activities are strongly associated with their abilities to localize to centrosomes. Among them, HDAC1, HDAC5 and SIRT1 show the highest suppressing activities, but each of them suppresses centrosome duplication and/or amplification with its unique mechanism.


Assuntos
Ciclo Celular/fisiologia , Centrossomo/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Acetilação , Linhagem Celular , Centrossomo/ultraestrutura , Ciclina A/genética , Ciclina A/metabolismo , Genes Reporter , Proteínas de Fluorescência Verde , Histona Desacetilases/genética , Histonas/genética , Humanos , Microscopia de Fluorescência , RNA Interferente Pequeno/genética , Transfecção
14.
Cell Cycle ; 11(15): 2931-46, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22833046

RESUMO

BRCA1, a product of a familial breast and ovarian cancer susceptibility gene, localizes to centrosomes and physically interacts with γ-tubulin, a key centrosomal protein for microtubule nucleation and anchoring at centrosomes. Here, we performed a rigorous analysis of centrosome localization of BRCA1, and found that BRCA1 is specifically associated with mother centrioles in unduplicated centrosomes, and daughter centrioles acquire BRCA1 prior to initiation of duplication, and thus duplicated centrosomes are both bound by BRCA1. We further found that BRCA1 suppresses centrosomal aster formation. In addition, we identified a new domain of BRCA1 critical for γ-tubulin binding, which confers not only its localization to centrosomes, but also its activity to suppress centrosomal aster formation.


Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Centríolos/metabolismo , Centrossomo/metabolismo , Tubulina (Proteína)/metabolismo , Proteína BRCA1/genética , Linhagem Celular Tumoral , Feminino , Proteínas de Fluorescência Verde , Células HeLa , Humanos , Células MCF-7 , Interferência de RNA , RNA Interferente Pequeno , Fuso Acromático/metabolismo
15.
Mol Cell Biol ; 32(14): 2823-36, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22586264

RESUMO

SIRT1 is a NAD(+)-dependent histone H4K16 deacetylase that controls several different normal physiologic and disease processes. Like most histone deacetylases, SIRT1 also deacetylates nonhistone proteins. Here, we show that two members of the MYST (MOZ, Ybf2/Sas3, Sas2, and TIP60) acetyltransferase family, hMOF and TIP60, are SIRT1 substrates. SIRT1 deacetylation of the enzymatic domains of hMOF and TIP60 inhibits their acetyltransferase activity and promotes ubiquitination-dependent degradation of these proteins. Importantly, immediately following DNA damage, the binding of SIRT1 to hMOF and TIP60 is transiently interrupted, with corresponding hMOF/TIP60 hyperacetylation. Lysine-to-arginine mutations in SIRT1-targeted lysines on hMOF and TIP60 repress DNA double-strand break repair and inhibit the ability of hMOF/TIP60 to induce apoptosis in response to DNA double-strand break. Together, these findings uncover novel pathways in which SIRT1 dynamically interacts with and regulates hMOF and TIP60 through deacetylation and provide additional mechanistic insights by which SIRT1 regulates DNA damage response.


Assuntos
Histona Acetiltransferases/metabolismo , Sirtuína 1/metabolismo , Substituição de Aminoácidos , Animais , Apoptose , Linhagem Celular , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Células HEK293 , Células HeLa , Histona Acetiltransferases/genética , Humanos , Lisina Acetiltransferase 5 , Camundongos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sirtuína 1/genética , Especificidade por Substrato , Ubiquitinação
16.
J Cell Biol ; 197(1): 19-26, 2012 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-22451695

RESUMO

Aurora A (AurA) is a major mitotic protein kinase involved in centrosome maturation and spindle assembly. Nucleophosmin/B23 (NPM) is a pleiotropic nucleolar protein involved in a variety of cellular processes including centrosome maturation. In the present study, we report that NPM is a strong activator of AurA kinase activity. NPM and AurA coimmunoprecipitate and colocalize to centrosomes in G2 phase, where AurA becomes active. In contrast with previously characterized AurA activators, NPM does not trigger autophosphorylation of AurA on threonine 288. NPM induces phosphorylation of AurA on serine 89, and this phosphorylation is necessary for activation of AurA. These data were confirmed in vivo, as depletion of NPM by ribonucleic acid interference eliminated phosphorylation of CDC25B on S353 at the centrosome, indicating a local loss of AurA activity. Our data demonstrate that NPM is a strong activator of AurA kinase activity at the centrosome and support a novel mechanism of activation for AurA.


Assuntos
Centrossomo/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Serina/metabolismo , Aurora Quinases , Células HeLa , Humanos , Proteínas Nucleares/genética , Nucleofosmina , Fosforilação
17.
Mol Cell Biol ; 31(23): 4720-34, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21947282

RESUMO

DNA methylation and histone acetylation/deacetylation are distinct biochemical processes that control gene expression. While DNA methylation is a common epigenetic signal that inhibits gene transcription, histone deacetylation similarly represses transcription but can be both an epigenetic and nonepigenetic phenomenon. Here we report that the histone deacetylase SIRT1 regulates the activities of DNMT1, a key enzyme responsible for DNA methylation. In mass spectrometry analysis, 12 new acetylated lysine sites were identified in DNMT1. SIRT1 physically associates with DNMT1 and can deacetylate acetylated DNMT1 in vitro and in vivo. Interestingly, deacetylation of different lysines on DNMT1 has different effects on the functions of DNMT1. For example, deacetylation of Lys1349 and Lys1415 in the catalytic domain of DNMT1 enhances DNMT1's methyltransferase activity, while deacetylation of lysine residues in the GK linker decreases DNMT1's methyltransferase-independent transcriptional repression function. Furthermore, deacetylation of all identified acetylated lysine sites in DNMT1 abrogates its binding to SIRT1 and impairs its capability to regulate cell cycle G(2)/M transition. Finally, inhibition of SIRT1 strengthens the silencing effects of DNMT1 on the expression of tumor suppressor genes ER-α and CDH1 in MDA-MB-231 breast cancer cells. Together, these results suggest that SIRT1-mediated deacetylation of DNMT1 is crucial for DNMT1's multiple effects in gene silencing.


Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Regulação da Expressão Gênica , Sirtuína 1/metabolismo , Acetilação , Animais , Pontos de Checagem do Ciclo Celular , Núcleo Celular/metabolismo , Células Cultivadas , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , Ensaios Enzimáticos , Expressão Gênica , Inativação Gênica , Inibidores de Histona Desacetilases/farmacologia , Humanos , Imunoprecipitação , Cinética , Camundongos , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Interferência de RNA , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
18.
Horm Cancer ; 2(2): 104-12, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21761333

RESUMO

The centrosome that functions as a microtubule organizing center of a cell plays a key role in formation of bipolar mitotic spindles. Cells normally have either one (unduplicated) or two (duplicated) centrosomes. However, loss of the mechanisms controlling the numeral integrity of centrosomes leads to centrosome amplification (presence of more than two centrosomes), primarily via overduplication or fragmentation of centrosomes, resulting in defective mitosis and consequentially chromosome instability. Centrosome amplification frequently occurs in various cancers, and is considered as a major cause of chromosome instability. It has recently been found that ROCK2 kinase plays a critical role in promotion of centrosome duplication and amplification. Considering that ROCK2 is activated by Rho protein, and Rho is the immediate downstream target of many growth and hormone receptors, it is possible that such receptors may rather directly affect centrosome duplication and amplification. Indeed, constitutive activation of the receptors known to signal to the Rho pathway leads to promotion of centrosome amplification and chromosome instability in the Rho-ROCK2 pathway-dependent manner. These observations reveal an unexplored, yet important, oncogenic activities of those receptors in carcinogenesis; destabilizing chromosomes through promotion of centrosome amplification via continual activation of the Rho-ROCK2 pathway.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Centrossomo/metabolismo , Neoplasias/metabolismo , Transdução de Sinais/fisiologia , Quinases Associadas a rho/metabolismo , Animais , Transformação Celular Neoplásica/patologia , Centrossomo/patologia , Humanos , Mitose/fisiologia
19.
Biochim Biophys Acta ; 1786(1): 15-23, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18472015

RESUMO

Centrosomes play a critical role in formation of bipolar mitotic spindles, an essential event for accurate chromosome segregation into daughter cells. Numeral abnormalities of centrosomes (centrosome amplification) occur frequently in cancers, and are considered to be the major cause of chromosome instability, which accelerates acquisition of malignant phenotypes during tumor progression. Loss or mutational inactivation of p53 tumor suppressor protein, one of the most common mutations found in cancers, results in a high frequency of centrosome amplification in part via allowing the activation of the cyclin-dependent kinase (CDK) 2-cyclin E (as well as CDK2-cyclin A) which is a key factor for the initiation of centrosome duplication. In this review, the role of centrosome amplification in tumor progression, and mechanistic view of how centrosomes are amplified in cells through focusing on loss of p53 and aberrant activities of CDK2-cyclins will be discussed.


Assuntos
Centrossomo/fisiologia , Quinases Ciclina-Dependentes/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Ciclina E/fisiologia , Quinase 2 Dependente de Ciclina/fisiologia , Fuso Acromático/patologia
20.
Nat Rev Cancer ; 7(12): 911-24, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18004399

RESUMO

Chromosome instability, which is equated to mitotic defects and consequential chromosome segregation errors, provides a formidable basis for the acquisition of further malignant phenotypes during tumour progression. Centrosomes have a crucial role in the formation of bipolar mitotic spindles, which are essential for accurate chromosome segregation. Mutations of certain oncogenic and tumour-suppressor proteins directly induce chromosome instability by disrupting the normal function and numeral integrity of centrosomes. How these proteins control centrosome duplication and function, and how their mutational activation and/or inactivation results in numeral and functional centrosome abnormalities, is discussed in this Review.


Assuntos
Centrossomo/ultraestrutura , Genes Supressores de Tumor , Neoplasias/genética , Oncogenes , Transporte Ativo do Núcleo Celular , Instabilidade Cromossômica/genética , Instabilidade Cromossômica/fisiologia , Ciclina G , Ciclina G1 , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Dano ao DNA , Humanos , Mitose/genética , Mitose/fisiologia , Mutação , Neoplasias/ultraestrutura , Oncogenes/genética
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