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Utilizing spin pumping, we present a comparative study of the spin-charge conversion in RuO_{2}(101) and RuO_{2}(110) films. RuO_{2}(101) shows a robust in-plane crystal-axis dependence, whereas RuO_{2}(110) exhibits an isotropic but stronger one. Symmetry-based analysis and first-principles calculations reveal that the spin-charge conversion in RuO_{2}(110) originates from the inverse spin Hall effect (ISHE) due to nodal lines splitting. In RuO_{2}(101), the ISHE also dominates although the inverse spin splitting effect (ISSE) may coexist. These findings, in sharp contrast to previously attributed ISSE, are further corroborated by the reciprocal relation between the spin pumping and the spin-torque ferromagnetic resonance measurements.
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In a joint effort of both experiments and first-principles calculations, we resolve a hotly debated controversy and provide a coherent picture on the pure spin transport between Ag/Bi and ferromagnets. We demonstrate a strong inverse Rashba-Edelstein effect (IREE) at the interface in between Ag/Bi with a ferromagnetic metal (FM) but not with a ferromagnetic insulator. This is in sharp contrast to the previously claimed IREE at Ag/Bi interface or inverse spin Hall effect dominated spin transport. A more than one order of magnitude modulation of IREE signal is realized for different Ag/Bi-FM interfaces, casting strong tunability and a new direction for searching efficient spintronics materials.
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Metabolic disorder is one of the most obvious pathophysiological characteristics of patients with severe burn or trauma, which leads to high mortality of patients with severe burn or trauma. Metabonomics is a newly developed subject which provides new research concepts and ideas for studying the changes of metabolism in a disease condition. Based on the analysis of group indicators, metabonomic technique not only can systematically study the change rules of metabolites, which helps to further clarify the pathophysiological mechanism of burn or trauma, but also is helpful to find some significant biomarkers with important clinical value so as to provide new insight for the therapy of burn or trauma. This paper reviews the research progress of application of metabonomics in the treatment of severe burn or trauma in recent years.
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Quemaduras/terapia , Metabolómica , Proteínas/uso terapéutico , Biomarcadores , Quemaduras/metabolismo , Humanos , Metabolómica/tendencias , Proteínas/metabolismoRESUMEN
Objective:To explore the clinical value of nasal endoscope combined with supporting laryngoscope surgery in the treatment of polyps of vocal cord. Method:Ninety-four patients with vocal cord polyps were randomly divided into the control group (47 cases) and the observation group (47 cases). The patients in the control group were treated with simply supporting laryngoscope surgery while the patients in the observation group were treated with nasal endoscope combined with supporting laryngoscope. The therapeutic effects, voice function changes before and after operation, complications and recurrence of the two groups were observed. Result:The total effective rate was 93.62% in the observation group, compared to 78.72% in the control group, the difference was statistically significant (P<0.05). The incidence of postoperative complications in the observation group was 8.51%, compared with 25.53% in the control group, the difference was statistically significant (P<0.05). Six months after operation, there was no recurrence in the observation group, but the recurrence rate in the control group was 4.26%. There was no significant difference between the two groups (P>0.05). 12 months after operation, the recurrence rate of the observation group was 2.13%, compared with 14.89% of the control group, the difference was statistically significant (P<0.05). Conclusion:Nasal endoscope combined with supporting laryngoscope for vocal cord polyps has a definite effect and can significantly improve the voice function of patients with high safety and low recurrence rate, which is worthy of promotion.î.
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Enfermedades de la Laringe , Laringoscopía , Pólipos , Pliegues Vocales , Humanos , Enfermedades de la Laringe/cirugía , Laringoscopios , Pólipos/cirugía , Calidad de la VozRESUMEN
Objective: To explore the relationship between endometrial thickness and clinical pregnancy outcomes in frozen-thawed embryo transfer cycles. Methods: A prospective study was performed for 1 475 frozen-thawed embryo transfer cycles at Peking University People's Hospital from January 2014 to December 2015. The patients were divided into different groups according to endometrial thickness of ovulation day in natural menstrual cycles or endometrial transformation day in hormone replacement cycles;patients with thin endometrium were enndometrial thickness ≤6 mm. Then the clinical pregnancy outcomes including clinical pregnancy rate, embryo implantation rate, abortion rate, multiple birth rate and live birth rate were analyzed. Results: In all, 1 475 frozen-thawed embryo transfer cycles were analyzed. The mean age of patients was (32.5±3.9) years old and mean endometrial thickness was (9.2±1.9) mm, and mean number of embryos was 2.03±0.37. The study included 518 (35.1%) natural menstrual cycles and 957 (64.9%) hormone replacement cycles. The number of embryo-transfer cycles and blastocyst-transfer cycles were respectively 700 (47.5%) and 775 (52.5%) . The overall clinical pregnancy rate, embryo implantation rate, abortion rate, multiple birth rate and live birth rate were 54.4%, 35.7%, 23.3%, 24.1%, 43.9%, respectively. The ectopic pregnancy rate in the study was 0.6%. In patients with thin endometrium,there were significant differences in 2 pronucleus count (P=0.016) and available embryo count (P=0.024) between cycles that resulted in pregnancy and those that did not;besides, the use of sildenafil and growth hormone did not improve pregnancy outcomes in patients with thin endometrium (P=0.183, P=0.400) . The clinical pregnancy rate, embryo implantation rate and live birth rate of embryo-transfer and blastocyst-transfer were similar in patients with thin endometrium (all P>0.05) . Conclusions: Patients with thin endometrium have poor pregnancy outcomes. The clinical pregnancy rate, embryo implantation rate and live birth rate of embryo-transfer and blastocyst-transfer are similar in patients with thin endometrium. Compared thin endometrium and non-thin endometrium patients, the clinical pregnancy rate and live birth rate of blastocysts have more substantial decline than those of embryos. Improving the quality of embryo could improve the pregnancy outcome of patients with thin endometrium. Sildenafil and growth hormone could not improve pregnancy outcome in patients with thin endometrium.
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Blastocisto , Implantación del Embrión , Transferencia de Embrión/métodos , Endometrio/anatomía & histología , Terapia de Reemplazo de Hormonas , Resultado del Embarazo , Adulto , Criopreservación , Femenino , Humanos , Ciclo Menstrual , Embarazo , Índice de Embarazo , Estudios ProspectivosRESUMEN
Single monolayer FeSe film grown on a Nb-doped SrTiO_{3}(001) substrate shows the highest superconducting transition temperature (T_{C}â¼100 K) among the iron-based superconductors (iron pnictides), while the T_{C} value of bulk FeSe is only â¼8 K. Although bulk FeSe does not show antiferromagnetic order, calculations suggest that the parent FeSe/SrTiO_{3} films are antiferromagnetic. Experimentally, because of a lack of a direct probe, the magnetic state of FeSe/SrTiO_{3} films remains mysterious. Here, we report direct evidence of antiferromagnetic order in the parent FeSe/SrTiO_{3} films by the magnetic exchange bias effect measurements. The magnetic blocking temperature is â¼140 K for a single monolayer film. The antiferromagnetic order disappears after electron doping.
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We clarify the physical origin of the dc voltage generation in a bilayer of a conducting polymer film and a micrometer-thick magnetic insulator Y_{3}Fe_{5}O_{12} (YIG) film under ferromagnetic resonance and/or spin wave excitation conditions. The previous attributed mechanism, the inverse spin Hall effect in the polymer [Nat. Mater. 12, 622 (2013)NMAACR1476-112210.1038/nmat3634], is excluded by two control experiments. We find an in-plane temperature gradient in YIG which has the same angular dependence with the generated voltage. Both vanish when the YIG thickness is reduced to a few nanometers. Thus, we argue that the dc voltage is governed by the Seebeck effect in the polymer, where the temperature gradient is created by the nonreciprocal magnetostatic surface spin wave propagation in YIG.
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Mice lacking genes involving in the DNA-damage response (DDR) are often tumor prone owing to genome instability caused by oncogenic challenges. Previous studies demonstrate that activating transcription factor 3 (ATF3), a common stress sensor, can activate the tumor suppressor p53 and regulate expression of p53 target genes upon DNA damage. However, whether ATF3 contributes to the maintenance of genome stability and tumor suppression remains unknown. Here we report that Atf3-deficient (Atf3-/-) mice developed spontaneous tumors, and died significantly earlier than wild-type (Atf3+/+) mice. Consistent with these results, Atf3-/- mouse embryonic fibroblasts (MEFs) had more aberrant chromosomes and micronuclei, and were genetically unstable. Whereas we demonstrated that ATF3 activated p53 and promoted its pro-apoptotic activity in mouse thymi and small intestines, the chromosomal instability caused by Atf3 deficiency was largely dependent on the regulation of p53 by ATF3. Interestingly, loss of Atf3 also promoted spontaneous tumorigenesis in Trp53+/- mice, but did not affect tumor formation in Trp53-/- mice. Our results thus provide the first genetic evidence linking ATF3 to the suppression of the early development of cancer, and underscore the importance of ATF3 in the maintenance of genome integrity.
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Factor de Transcripción Activador 3/metabolismo , Carcinogénesis/genética , Predisposición Genética a la Enfermedad , Inestabilidad Genómica , Neoplasias/genética , Factor de Transcripción Activador 3/genética , Animales , Apoptosis/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Daño del ADN , Femenino , Fibroblastos , Genes Supresores de Tumor , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/mortalidad , Neoplasias/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Diverse factors have been identified as potent EMT inducers in ovarian cancer. However, molecular mechanism sustaining EMT of ovarian cancer cells remains elusive. Here we show that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells. Consistent with the role of SOS1/EPS8/ABI1 complex as a Rac1-specific guanine nucleotide exchange factor, depleting Rac1 results in the loss of most of mesenchymal traits in mesenchymal-like ovarian cancer cells, whereas expressing constitutively active Rac1 leads to EMT in epithelial-like ovarian cancer cells. With the aid of clinically tested inhibitors targeting various EMT-associated signaling pathways, we show that only combined treatment of mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and Src inhibitors can abolish constitutively active Rac1-led EMT and mesenchymal traits displayed by mesenchymal-like ovarian cancer cells. Further experiments also reveal that EMT can be induced in epithelial-like ovarian cancer cells by co-expressing constitutively active MEK1 and Src rather than either alone. As the activities of Erk and Src are higher in ovarian cancer cells with constitutively active Rac1, we conclude that Rac1 sustains ovarian cancer cell EMT through simultaneous activation of MEK1/2 and Src signaling pathways. Importantly, we demonstrate that combined use of MEK1/2 and Src inhibitors effectively suppresses development of intraperitoneal xenografts and prolongs the survival of ovarian cancer-bearing mice. This study suggests that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression.
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Transición Epitelial-Mesenquimal , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/metabolismo , Transducción de Señal , Proteína de Unión al GTP rac1/metabolismo , Familia-src Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Línea Celular Tumoral , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteínas de Homeodominio/metabolismo , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Represoras/metabolismo , Proteína SOS1/metabolismo , Factores de Transcripción Twist/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismoRESUMEN
Utilizing epitaxial Co2Fe1-xMnxAl full-Heusler alloy films on GaAs (001), we address the controversy over the analysis for the split hysteresis loop which is commonly found in systems consisting of both uniaxial and fourfold anisotropies. Quantitative comparisons are carried out on the values of the twofold and fourfold anisotropy fields obtained with ferromagnetic resonance and vibrating sample magnetometer measurements. The most suitable model for describing the split hysteresis loop is identified. In combination with the component resolved magnetization measurements, these results provide compelling evidences that the switching is caused by the domain wall nucleation and movements with the switching fields centered at the point where the energy landscape shows equal minima for magnetization orienting near the easy axis and the field supported hard axis.
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Steroid sex hormones can induce prostate carcinogenesis, and are thought to contribute to the development of prostate cancer during aging. However, the mechanism for hormone-induced prostate carcinogenesis remains elusive. Here, we report that activating transcription factor 3 (ATF3)-a broad stress sensor-suppressed hormone-induced prostate carcinogenesis in mice. Although implantation of testosterone and estradiol (T+E2) pellets for 2 months in wild-type mice rarely induced prostatic intraepithelial neoplasia (PIN) in dorsal prostates (one out of eight mice), the loss of ATF3 led to the appearance of not only PIN but also invasive lesions in almost all examined animals. The enhanced carcinogenic effects of hormones on ATF3-deficient prostates did not appear to be caused by a change in estrogen signaling, but were more likely a consequence of elevated androgen signaling that stimulated differentiation of prostatic basal cells into transformation-preferable luminal cells. Indeed, we found that hormone-induced lesions in ATF3-knockout mice often contained cells with both basal and luminal characteristics, such as p63(+) cells (a basal-cell marker) showing luminal-like morphology, or cells double-stained with basal (CK5(+)) and luminal (CK8(+)) markers. Consistent with these findings, low ATF3 expression was found to be a poor prognostic marker for prostate cancer in a cohort of 245 patients. Our results thus support that ATF3 is a tumor suppressor in prostate cancer.
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Factor de Transcripción Activador 3/metabolismo , Carcinogénesis/metabolismo , Células Epiteliales/metabolismo , Queratina-5/metabolismo , Queratina-8/metabolismo , Próstata/metabolismo , Factor de Transcripción Activador 3/genética , Animales , Western Blotting , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular , Línea Celular Tumoral , Células Epiteliales/efectos de los fármacos , Estradiol/toxicidad , Hormonas/toxicidad , Humanos , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Próstata/efectos de los fármacos , Próstata/patología , Neoplasia Intraepitelial Prostática/inducido químicamente , Neoplasia Intraepitelial Prostática/genética , Neoplasia Intraepitelial Prostática/metabolismo , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Interferencia de ARN , Testosterona/toxicidadRESUMEN
We address the controversy over the spin transport mechanism in Alq3 utilizing spin pumping in the Y3Fe5O12/Alq3/Pd system. An unusual angular dependence of the inverse spin Hall effect is found. It, however, disappears when the microwave magnetic field is fully in the sample plane, excluding the presence of the Hanle effect. Together with the quantitative temperature-dependent measurements, these results provide compelling evidence that the pure spin current transport in Alq3 is dominated by the exchange-mediated mechanism.
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Low dimensional nanostructures have attracted attention due to their rich physical properties and potential applications. The essential factor for their functionality is their electronic properties, which can be modified by quantum confinement. Here the electronic states of Gd atom trapped in open Fe corrals on Ag(111) were studied via scanning tunneling spectroscopy. A single spectroscopic peak above the Fermi level is observed after Gd adatoms are trapped inside Fe corrals, while two peaks appear in empty corrals. The single peak position is close to the higher energy peak of the empty corrals. These findings, attributed to quantum confinement of the corrals and Gd structures trapped inside, are supported by tight-binding calculations. This demonstrates and provides insights into atom trapping in open corrals of various diameters, giving an alternative approach to modify the properties of nano-objects.
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Gadolinio/química , Nanoestructuras/química , Hierro/química , Microscopía de Túnel de Rastreo/métodos , Nanotecnología/métodos , Plata/química , Análisis Espectral/métodosRESUMEN
Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (for example, proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression is frequently found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here, we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas the oncogenic stress elicited by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation and promoted cell survival, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, the loss of ATF3 promoted activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by single guided RNA-mediated targeting activated AKT and increased matrix metalloproteinase-9 expression. Our results thus link ATF3 to the AKT signaling, and suggest that ATF3 is a tumor suppressor for the major subset of prostate cancers harboring dysfunctional Pten.
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Factor de Transcripción Activador 3/fisiología , Fosfohidrolasa PTEN/fisiología , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción Activador 3/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Activación Enzimática , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/metabolismo , Transducción de SeñalRESUMEN
MEIS2 has an important role in development and organogenesis, and is implicated in the pathogenesis of human cancer. The molecular basis of MEIS2 action in tumorigenesis is not clear. Here, we show that MEIS2 is highly expressed in human neuroblastoma cell lines and is required for neuroblastoma cell survival and proliferation. Depletion of MEIS2 in neuroblastoma cells leads to M-phase arrest and mitotic catastrophe, whereas ectopic expression of MEIS2 markedly enhances neuroblastoma cell proliferation, anchorage-independent growth, and tumorigenicity. Gene expression profiling reveals an essential role of MEIS2 in maintaining the expression of a large number of late cell-cycle genes, including those required for DNA replication, G2-M checkpoint control and M-phase progression. Importantly, we identify MEIS2 as a transcription activator of the MuvB-BMYB-FOXM1 complex that functions as a master regulator of cell-cycle gene expression. Further, we show that FOXM1 is a direct target gene of MEIS2 and is required for MEIS2 to upregulate mitotic genes. These findings link a developmentally important gene to the control of cell proliferation and suggest that high MEIS2 expression is a molecular mechanism for high expression of mitotic genes that is frequently observed in cancers of poor prognosis.
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División Celular , Proliferación Celular , Supervivencia Celular , Proteínas de Homeodominio/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/fisiopatología , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteínas de Homeodominio/genética , Humanos , Neuroblastoma/genética , Factores de Transcripción/genéticaRESUMEN
A Skyrmion crystal typically arises from helical spin structures induced by the Dzyaloshinskii-Moriya interaction. Experimentally its physical exploration has been impeded because it is a rarity and is found only within a narrow temperature and magnetic field range. We present a method for the assembly of a two-dimensional Skyrmion crystal based upon a combination of a perpendicularly magnetized film and nanopatterned arrays of magnetic vortices that are geometrically confined within nanodisks. The practical feasibility of the method is validated by micromagnetic simulations and computed Skyrmion number per unit cell. We also quantify a wide range in temperature and field strength over which the Skyrmion crystal can be stabilized without the need for any intrinsic Dzyaloshinskii-Moriya interactions, which otherwise is needed to underpin the arrangement as is the case in the very few known Skyrmion crystal cases. Thus, our suggested scheme involves a qualitative breakthrough that comes with a substantial quantitative advance.
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Sustained urokinase-type plasminogen activator (uPA) expression is detected in aggressive breast tumors. Although uPA can be transiently upregulated by diverse extracellular stimuli, sustained, but not transiently upregulated uPA expression contributes to breast cancer invasion/metastasis. Unfortunately, how sustained uPA expression is achieved in invasive/metastatic breast cancer cells is unknown. Here, we show that sustained and transiently upregulated uPA expression are regulated by distinct mechanisms. Using a collection of transcription factor-targeted small-interfering RNAs, we discovered that interleukin enhancer-binding factor 3 (ILF3) is required for sustained uPA expression. Two discrete mechanisms mediate ILF3 action. The first is that ILF3 activates uPA transcription by binding to the CTGTT sequence in the nucleotides -1004â¼-1000 of the uPA promoter; the second is that ILF3 inhibits the processing of uPA mRNA-targeting primary microRNAs (pri-miRNAs). Knockdown of ILF3 led to significant reduction in in vitro cell growth/migration/invasion and in vivo breast tumor development. Importantly, immunohistochemistry (IHC) showed that nuclear ILF3, but not cytoplasmic ILF3 staining correlates with elevated uPA level and higher grades of human breast tumor specimens. Nuclear localization of ILF3 highlights the role of ILF3 in sustained uPA expression as a transcription activator and pri-miRNA processing blocker. In conclusion, this study shows that ILF3 promotes breast tumorigenicity by regulating sustained uPA expression.
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Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Proteínas del Factor Nuclear 90/genética , Activador de Plasminógeno de Tipo Uroquinasa/genética , Animales , Western Blotting , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/genética , Supervivencia Celular/genética , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Desnudos , MicroARNs/genética , Proteínas del Factor Nuclear 90/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante Heterólogo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Embryonal cancer can arise from postnatally persistent embryonal remnant or rest cells, which are uniquely characterized by the absence of p53 mutations. Perinatal overexpression of the MycN oncoprotein in embryonal cancer precursor cells causes postnatal rests, and later tumor formation through unknown mechanisms. However, overexpression of Myc in adult tissues normally activates apoptosis and/or senescence signals as an organismal defense mechanism against cancer. Here, we show that perinatal neuroblastoma precursor cells exhibited a transiently diminished p53 response to MycN oncoprotein stress and resistance to trophic factor withdrawal, compared with their adult counterpart cells from the TH-MYCN(+/+) transgenic mouse model of neuroblastoma. The adult stem cell maintenance factor and Polycomb group protein, Bmi1 (B-cell-specific Moloney murine leukemia virus integration site), had a critical role at neuroblastoma initiation in the model, by repressing p53 responses in precursor cells. We further show in neuroblastoma tumor cells that Bmi1 could directly bind p53 in a complex with other Polycomb complex proteins, Ring1A or Ring1B, leading to increased p53 ubiquitination and degradation. Repressed p53 signal responses were also seen in precursor cells for other embryonal cancer types, medulloblastoma and acute lymphoblastic leukemia. Collectively, these date indicate a general mechanism for p53 inactivation in some embryonal cell types and consequent susceptibility to MycN oncogenesis at the point of embryonal tumor initiation.
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Neoplasias de Células Germinales y Embrionarias/patología , Células Madre Neoplásicas/patología , Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Complejo Represivo Polycomb 1/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Estrés Fisiológico , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Humanos , Leucemia/metabolismo , Leucemia/patología , Meduloblastoma/metabolismo , Meduloblastoma/patología , Ratones , Proteína Proto-Oncogénica N-Myc , Neoplasias de Células Germinales y Embrionarias/metabolismo , Células Madre Neoplásicas/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patología , Poliubiquitina/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Estabilidad Proteica , Proteolisis , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal , UbiquitinaciónRESUMEN
The Polycomb transcription repressor BMI1 is highly expressed in human neuroblastomas and is required for the clonogenic self-renewal and tumorigenicity of human neuroblastoma cell lines. The molecular basis of BMI1 action in neuroblastoma cells is not well understood. Here we report that BMI1 has a critical role in stabilizing cyclin E1 by repressing the expression of FBXW7, a substrate-recognition subunit of the SCF E3 ubiquitin ligase that targets cyclin E1 for degradation. BMI1 binds to the FBXW7 locus in vivo and represses its mRNA expression. Overexpression of cyclin E1 or abrogation of FBXW7 induction rescues the cell-death phenotype of BMI1 knockdown. Moreover, MYCN, an oncoprotein in the pathogenesis of high-risk neuroblastomas, is able to counteract the death-inducing effect of BMI1 knockdown by activating CCNE1 transcription. We further show that high cyclin E1 expression is associated with Stage 4 neuroblastomas and poor prognosis in patients. These findings suggest a molecular mechanism for the oncogenic activity of BMI1 and MYCN in neuroblastoma pathogenesis and progression by maintaining cyclin E1 levels.