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Hippo signaling controls organ size and tumor progression through a conserved pathway leading to nuclear translocation of the transcriptional effector Yki/Yap/Taz. Most of our understanding of Hippo signaling pertains to its cytoplasmic regulation, but how the pathway is controlled in the nucleus remains poorly understood. Here we uncover an evolutionarily conserved mechanism by which CDK7 promotes Yki/Yap/Taz stabilization in the nucleus to sustain Hippo pathway outputs. We found that a modular E3 ubiquitin ligase complex CRL4DCAF12 binds and targets Yki/Yap/Taz for ubiquitination and degradation, whereas CDK7 phosphorylates Yki/Yap/Taz at S169/S128/S90 to inhibit CRL4DCAF12 recruitment, leading to Yki/Yap/Taz stabilization. As a consequence, inactivation of CDK7 reduced organ size and inhibited tumor growth, which could be reversed by restoring Yki/Yap activity. Our study identifies an unanticipated layer of Hippo pathway regulation, defines a novel mechanism by which CDK7 regulates tissue growth, and implies CDK7 as a drug target for Yap/Taz-driven cancer.
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Carcinogénesis/genética , Quinasas Ciclina-Dependientes/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimología , Drosophila melanogaster/metabolismo , Proteínas Nucleares/metabolismo , Transactivadores/metabolismo , Animales , Antineoplásicos/farmacología , Carcinogénesis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Quinasas Ciclina-Dependientes/genética , Drosophila melanogaster/genética , Activación Enzimática , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/fisiopatología , Ratones , Tamaño de los Órganos/genética , Fenilendiaminas/farmacología , Proteolisis , Pirimidinas/farmacología , Proteínas Señalizadoras YAP , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
Hippo signaling restricts tumor growth by inhibiting the oncogenic potential of YAP/TAZ-TEAD transcriptional complex. Here, we uncover a context-dependent tumor suppressor function of YAP in androgen receptor (AR) positive prostate cancer (PCa) and show that YAP impedes AR+ PCa growth by antagonizing TEAD-mediated AR signaling. TEAD forms a complex with AR to enhance its promoter/enhancer occupancy and transcriptional activity. YAP and AR compete for TEAD binding and consequently, elevated YAP in the nucleus disrupts AR-TEAD interaction and prevents TEAD from promoting AR signaling. Pharmacological inhibition of MST1/2 or LATS1/2, or transgenic activation of YAP suppressed the growth of PCa expressing therapy resistant AR splicing variants. Our study uncovers an unanticipated crosstalk between Hippo and AR signaling pathways, reveals an antagonistic relationship between YAP and TEAD in AR+ PCa, and suggests that targeting the Hippo signaling pathway may provide a therapeutical opportunity to treat PCa driven by therapy resistant AR variants.
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Neoplasias de la Próstata , Factores de Transcripción , Masculino , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Señalizadoras YAP , Transducción de Señal , Neoplasias de la Próstata/genéticaRESUMEN
After binding to its cell surface receptor angiotensin converting enzyme 2 (ACE2), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell through directly fusing with plasma membrane (cell surface pathway) or undergoing endocytosis traveling to lysosome/late endosome for membrane fusion (endocytic pathway). However, the endocytic entry regulation by host cell remains elusive. Recent studies show ACE2 possesses a type I PDZ binding motif (PBM) through which it could interact with a PDZ domain-containing protein such as sorting nexin 27 (SNX27). In this study, we determined the ACE2-PBM/SNX27-PDZ complex structure, and, through a series of functional analyses, we found SNX27 plays an important role in regulating the homeostasis of ACE2 receptor. More importantly, we demonstrated SNX27, together with retromer complex (the core component of the endosomal protein sorting machinery), prevents ACE2/virus complex from entering lysosome/late endosome, resulting in decreased viral entry in cells where the endocytic pathway dominates. The ACE2/virus retrieval mediated by SNX27-retromer could be considered as a countermeasure against invasion of ACE2 receptor-using SARS coronaviruses.
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Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/metabolismo , Endosomas/metabolismo , SARS-CoV-2 , Nexinas de Clasificación/química , COVID-19/virología , Línea Celular , Línea Celular Tumoral , Membrana Celular/metabolismo , Cristalografía por Rayos X , Citosol/metabolismo , Endocitosis , Perfilación de la Expresión Génica , Células HEK293 , Células HeLa , Homeostasis , Humanos , Lentivirus , Lisosomas/metabolismo , Péptidos/química , Unión Proteica , Conformación Proteica , Dominios Proteicos , Nexinas de Clasificación/metabolismo , Internalización del VirusRESUMEN
Organic luminescent materials are indispensable in optoelectronic displays and solid-state luminescence applications. Compared with single-component, multi-component crystalline materials can improve optoelectronic characteristics. This work forms a series of full-spectrum tunable luminescent charge-transfer (CT) cocrystals ranging from 400 to 800 nm through intermolecular collaborative self-assembly. What is even more interesting is that o-TCP-Cor(x)-Pe(1-x), p-TCP-Cor(x)-Pe(1-x), and o-TCP-AN(x)-TP(1-x) alloys are prepared based on cocrystals by doping strategies, which correspondingly achieve the stepless color change from blue (CIE [0.22, 0.44]) to green (CIE [0.16, 0.14]), from green (CIE [0.27, 0.56]) to orange (CIE [0.58, 0.42]), from yellow (CIE [0.40, 0.57]) to red (CIE [0.65, 0.35]). The work provides an efficient method for precisely synthesizing new luminescent organic semiconductor materials and lays a solid foundation for developing advanced organic solid-state displays.
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The field of supramolecular metal-organic cage catalysis has grown rapidly in recent years. However, theoretical studies regarding the reaction mechanism and reactivity and selectivity controlling factors for supramolecular catalysis are still underdeveloped. Herein, we demonstrate a detailed density functional theory study on the mechanism, catalytic efficiency, and regioselectivity of the Diels-Alder reaction in bulk solution and within two [Pd6L4]12+ supramolecular cages. Our calculations are consistent with experiments. The origins of the catalytic efficiency of the bowl-shaped cage 1 have been elucidated to be the host-guest stabilization of the transition states and the favorable entropy effect. The reasons for the switch of the regioselectivity from 9,10-addition to 1,4-addition within the octahedral cage 2 were attributed to the confinement effect and the noncovalent interactions. This work would shed light on the understanding of [Pd6L4]12+ metallocage-catalyzed reactions and provide a detailed mechanistic profile otherwise difficult to obtain from experiments. The findings of this study could also aid to the improvement and development of more efficient and selective supramolecular catalysis.
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BACKGROUND & AIMS: Primary liver tumors comprise distinct subtypes. A subset of intrahepatic cholangiocarcinoma (iCCA) can arise from cell fate reprogramming of mature hepatocytes in mouse models. However, the underpinning of cell fate plasticity during hepatocarcinogenesis is still poorly understood, hampering therapeutic development for primary liver cancer. As YAP activation induces liver tumor formation and cell fate plasticity, we investigated the role of Sox9, a transcription factor downstream of Yap activation that is expressed in biliary epithelial cells (BECs), in Yap-induced cell fate plasticity during hepatocarcinogenesis. METHODS: To evaluate the function of Sox9 in YAP-induced hepatocarcinogenesis in vivo, we used several genetic mouse models of inducible hepatocyte-specific YAP activation with simultaneous Sox9 removal. Cell fate reprogramming was determined by lineage tracing and immunohistochemistry. The molecular mechanism underlying Yap and Sox9 function in hepatocyte plasticity was investigated by transcription and transcriptomic analyses of mouse and human liver tumors. RESULTS: Sox9, a marker of liver progenitor cells (LPCs) and BECs, is differentially required in YAP-induced stepwise hepatocyte programming. While Sox9 has a limited role in hepatocyte dedifferentiation to LPCs, it is required for BEC differentiation from LPCs. YAP activation in Sox9-deficient hepatocytes resulted in more aggressive HCC with enhanced Yap activity at the expense of iCCA-like tumors. Furthermore, we showed that 20% of primary human liver tumors were associated with a YAP activation signature, and tumor plasticity is highly correlated with YAP activation and SOX9 expression. CONCLUSION: Our data demonstrated that Yap-Sox9 signaling determines hepatocyte plasticity and tumor heterogeneity in hepatocarcinogenesis in both mouse and human liver tumors. We identified Sox9 as a critical transcription factor required for Yap-induced hepatocyte cell fate reprogramming during hepatocarcinogenesis. LAY SUMMARY: Sox9, a marker of liver progenitor cells and bile duct lining cells, is a downstream target of YAP protein activation. Herein, we found that YAP activation in hepatocytes leads to a transition from mature hepatocytes to liver progenitor cells and then to bile duct lining cells. Sox9 is required in the second step during mouse hepatocarcinogenesis. We also found that human YAP and SOX9 may play similar roles in liver cancers.
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Carcinoma Hepatocelular/genética , Diferenciación Celular/genética , Neoplasias Hepáticas/fisiopatología , Transducción de Señal/genética , Animales , Carcinoma Hepatocelular/fisiopatología , Modelos Animales de Enfermedad , Hepatocitos/metabolismo , Hepatocitos/fisiología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Ratones , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Proteínas Señalizadoras YAP/genética , Proteínas Señalizadoras YAP/metabolismoRESUMEN
BACKGROUND: Triple negative breast cancer (TNBC) is one of the most lethal breast cancer subtypes. Due to a lack of effective therapeutic targets, chemotherapy is still the main medical treatment for TNBC patients. Thus, it is important and necessary to find new therapeutic targets for TNBC. Recent genomic studies implicated the Hippo / Yap signal is over activated in TNBC, manifesting it plays a key role in TNBC carcinogenesis and cancer progression. RBCK1 was firstly identified as an important component for linear ubiquitin assembly complex (LUBAC) and facilitates NFKB signaling in immune response. Further studies showed RBCK1 also facilitated luminal type breast cancer growth and endocrine resistance via trans-activation estrogen receptor alpha. METHODS: RBCK1 and YAP protein expression levels were measured by western blotting, while the mRNA levels of YAP target genes were measured by RT-PCR. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of Hippo signaling activity was accomplished with luciferase assays, RT-PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect YAP protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the YAP protein. RESULTS: In our current study, our data revealed an opposite function for RBCK1 in TNBC progression. RBCK1 over-expression inhibited TNBC cell progression in vitro and in vivo, while RBCK1 depletion promoted TNBC cell invasion. The whole genomic expression profiling showed that RBCK1 depletion activated Hippo/YAP axis. RBCK1 depletion increased YAP protein level and Hippo target gene expression in TNBC. The molecular biology studies confirmed that RBCK1 could bind to YAP protein and enhance the stability of YAP protein by promoting YAP K48-linked poly-ubiquitination at several YAP lysine sites (K76, K204 and K321). CONCLUSION: Our study revealed the multi-faced RBCK1 function in different subtypes of breast cancer patients and a promising therapeutic target for TNBC treatment. Video abstract.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/metabolismo , Receptor alfa de Estrógeno/metabolismo , Lisina , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Ubiquitina-Proteína Ligasas , ARN Mensajero , Ubiquitinas , Proliferación CelularRESUMEN
Oestrogen receptor α (ERα) is overexpressed in two-thirds of all breast cancer cases and is involved in breast cancer development and progression. Although ERα -positive breast cancer can be effectively treated by endocrine therapy, endocrine resistance is an urgent clinical problem. Thus, further understanding of the underlying mechanisms involved in ERα signalling is critical in dealing with endocrine resistance in patients with breast cancer. In the present study, unbiased RNA sequence analysis was conducted between the MCF-7 and MCF-7 tamoxifen-resistant (LCC2) cell lines in order to identify differentially expressed genes. The whole transcriptomic data indicated that the JAK-STAT pathway is markedly up-regulated, particularly the ISGF3 complex. As the critical effectors, STAT1 and IRF9 were up-regulated 5- and 20-fold, respectively, in LCC2 cells. The biological experiments indicated that STAT1 is important for ERα signalling. Depletion of STAT1 or inhibition of STAT1 function significantly decreased levels of ERα protein, ERα -target gene expression and cell proliferation in both the MCF-7 and LCC2 cell lines. Chromatin immunoprecipitation revealed that ERα transcription is associated with STAT1 recruitment to the ERα promoter region, suggesting that transcriptional regulation is one mechanism by which STAT1 regulates ERα mRNA levels and ERα signalling in breast cancer cells. The present study reveals a possible endocrine-resistant mechanism by which STAT1 modulates ERα signalling and confers tamoxifen resistance. Targeting of STAT1 is a potential treatment strategy for endocrine-resistant breast cancers.
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Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Factor de Transcripción STAT1/genética , Transcripción Genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Subunidad alfa del Factor 3 de Genes Estimulados por el Interferón/genética , Células MCF-7 , Transducción de Señal/efectos de los fármacos , Tamoxifeno/farmacologíaRESUMEN
It has been reported that some small noncoding RNAs are involved in the regulation of insulin sensitivity. However, whether long noncoding RNAs also participate in the regulation of insulin sensitivity is still largely unknown. We identified and characterized a long noncoding RNA, regulator of insulin sensitivity and autophagy (Risa), which is a poly(A)(+) cytoplasmic RNA. Overexpression of Risa in mouse primary hepatocytes or C2C12 myotubes attenuated insulin-stimulated phosphorylation of insulin receptor, Akt, and Gsk3ß, and knockdown of Risa alleviated insulin resistance. Further studies showed that overexpression of Risa in hepatocytes or myotubes decreased autophagy, and knockdown of Risa up-regulated autophagy. Moreover, knockdown of Atg7 or -5 significantly inhibited the effect of knockdown of Risa on insulin resistance, suggesting that knockdown of Risa alleviated insulin resistance via enhancing autophagy. In addition, tail vein injection of adenovirus to knock down Risa enhanced insulin sensitivity and hepatic autophagy in both C57BL/6 and ob/ob mice. Taken together, the data demonstrate that Risa regulates insulin sensitivity by affecting autophagy and suggest that Risa is a potential target for treating insulin-resistance-related diseases.-Wang, Y., Hu, Y., Sun, C., Zhuo, S., He, Z., Wang, H., Yan, M., Liu, J., Luan, Y., Dai, C., Yang, Y., Huang, R., Zhou, B., Zhang, F., Zhai, Q. Down-regulation of Risa improves insulin sensitivity by enhancing autophagy.
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Autofagia/fisiología , Regulación hacia Abajo/fisiología , Regulación de la Expresión Génica/fisiología , Resistencia a la Insulina/fisiología , ARN Largo no Codificante/metabolismo , Animales , Técnicas de Silenciamiento del Gen , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , ARN Largo no Codificante/genéticaRESUMEN
Three-dimensional hierarchical porous graphene/carbon composite was successfully synthesized from a solution of graphene oxide and a phenolic resin by using a facile and efficient method. The morphology, structure, and surface property of the composite were investigated intensively by a variety of means such as scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption, Raman spectroscopy, and Fourier transform infrared spectroscopy (FTIR). It is found that graphene serves as a scaffold to form a hierarchical pore texture in the composite, resulting in its superhigh surface area of 2034â m(2) g(-1), thin macropore wall, and high conductivity (152â S m(-1)). As evidenced by electrochemical measurements in both EMImBF4 ionic liquid and KOH electrolyte, the composite exhibits ideal capacitive behavior, high capacitance, and excellent rate performance due to its unique structure. In EMImBF4 , the composite has a high energy density of up to 50.1â Wh kg(-1) and also possesses quite stable cycling stability at 100 °C, suggesting its promising application in high-temperature supercapacitors. In KOH electrolyte, the specific capacitance of this composite can reach up to an unprecedented value of 186.5â F g(-1), even at a very high current density of 50â A g(-1), suggesting its prosperous application in high-power applications.
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BACKGROUND: Inhalation of chemotherapeutic drugs directly into the lungs augments the drug exposure to lung cancers. The inhalation of free drugs however results in over exposure and causes severe adverse effect to normal cells. In the present study, epidermal growth factor (EGF)-modified gelatin nanoparticles (EGNP) was developed to administer doxorubicin (DOX) to lung cancers. RESULTS: The EGNP released DOX in a sustained manner and effectively internalized in EGFR overexpressing A549 and H226 lung cancer cells via a receptor-mediated endocytosis. In vitro cytotoxicity assay showed that EGNP effectively inhibited the growth of A549 and H226 cells in a dose-dependent manner. In vivo biocompatibility study showed that both GNP and EGNP did not activate the inflammatory response and had a low propensity to cause immune response. Additionally, EGNP maintained a high therapeutic concentration in lungs throughout up to 24 h comparing to that of free drug and GNP, implying the effect of ligand-targeted tumor delivery. Mice treated with EGNP remarkably suppressed the tumor growth (~90% tumor inhibition) with 100% mice survival rate. Furthermore, inhalation of EGNP resulted in elevated levels of cleaved caspase-3 (apoptotic marker), while MMP-9 level significantly reduced comparing to that of control group. CONCLUSIONS: Overall, results suggest that EGF surface-modified nanocarriers could be delivered to lungs via inhalation and controlled delivery of drugs in the lungs will greatly improve the therapeutic options in lung cancer therapy. This ligand-targeted nanoparticulate system could be promising for the lung cancer treatment.
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Antineoplásicos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas/administración & dosificación , Metástasis de la Neoplasia/tratamiento farmacológico , Animales , Caspasa 3/metabolismo , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Hippo pathway functions as a tumor suppressor pathway by inhibiting the oncogenic potential of pathway effectors YAP/TAZ. However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCC). Here we show that YAP blocks NF-κB signaling in ccRCC to inhibit cancer cell growth. Mechanistically, YAP inhibits the expression of ZHX2, a critical p65 co-factor in ccRCC. Furthermore, YAP competes with ZHX2 for binding to p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and p65, leading to diminished NF-κB target gene expression. Pharmacological inhibition of Hippo/MST1/2 blocked NF-κB transcriptional program and suppressed ccRCC cancer cell growth, which can be rescued by ZHX2/p65 overexpression. Our study uncovers a novel crosstalk between the Hippo and NF-κB pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hippo pathway may provide a therapeutical opportunity for ccRCC treatment.
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Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER+) breast cancer. We find that inhibition of Hippo/MST1/2 or activation of YAP blocks the ERα transcriptional program and ER+ breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ERα to increase its promoter/enhancer occupancy whereas YAP inhibits ERα/TEAD interaction, decreases ERα occupancy on its target promoters/enhancers, and promotes ERα degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ERα gene (ESR1). Consistently, high levels of YAP correlate with good prognosis of ER+ breast cancer patients. Finally, we find that pharmacological inhibition of Hippo/MST1/2 impeded tumor growth driven by hormone therapy resistant ERα mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ERα mutants.
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Neoplasias de la Mama , Receptor alfa de Estrógeno , Neoplasias de la Mama/patología , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Hormonas , Humanos , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The evidence regarding the impact of the scores on healthy eating indices on the risk of cardiovascular events among patients with type 2 diabetes (T2D) is limited. As such, in this study, we examined the associations of adherence to the Chinese and American dietary guidelines and the risk of cardiovascular disease (CVD) among Chinese individuals with T2D. We conducted a 1:1 age- and sex-matched case−control study based on a Chinese population. We used a structured questionnaire and a validated 79-item food-frequency questionnaire to collect general information and dietary intake information, and calculated the Chinese Healthy Eating Index (CHEI) and the Healthy Eating Index-2015 (HEI-2015). As participants, we enrolled a total of 419 pairs of hospital-based CVD cases and controls, all of whom had T2D. We found a significant inverse association between diet quality scores on the CHEI and HEI-2015 and the risk of CVD. The adjusted odds ratios (95% confidence interval) per five-score increment were 0.68 (0.61, 0.76) in the CHEI and 0.60 (0.52, 0.70) in the HEI-2015. In stratified analyses, the protective associations remained significant in the subgroups of sex, BMI, smoking status, tea-drinking, hypertension state, dyslipidemia state, T2D duration, and medical nutrition therapy knowledge (all p < 0.05). These findings suggest that a higher CHEI or HEI-2015 score, representing a higher-quality diet relative to the most recent Chinese or American dietary guidelines, was associated with a decreased risk of CVD among Chinese patients with T2D.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Estudios de Casos y Controles , China/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Dieta/efectos adversos , Humanos , Política NutricionalRESUMEN
The tumor suppressor P53 plays critical role in preventing cancer. P53 is rarely mutated and remains functional in luminal-type breast cancer(1). According to current knowledge, wild-type P53 function is tightly controlled by posttranslational modifications, such as ubiquitination. Several ubiquitin ligases have been shown to regulate P53 ubiquitination and protein stability. Here, we report that RNF187, a RING family ubiquitin ligase, facilitates breast cancer growth and inhibits apoptosis by modulating P53 signaling. RNF187 expression was elevated in breast cancer and correlated with breast cancer survival only in the P53 wild-type groups. Bioinformatic analysis showed that the expression of RNF187 was negatively correlated with the expression of P53 target genes, such as IGFBP3 and FAS, in breast cancer. RNF187 depletion inhibited breast cancer growth and facilitated cell death. RNA sequencing analysis indicated that RNF187 could be an important modulator of P53 signaling. Further experiments showed that RNF187 interacts with P53 and promotes its degradation by facilitating its polyubiquitination in breast cancer cells. Interestingly, the in vitro ubiquitin assay showed that RNF187 can directly ubiquitinate P53 in a manner independent of MDM2. These findings reveal a novel direct P53 regulator and a potential therapeutic target for breast cancer.
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Neoplasias de la Mama , Transactivadores , Ubiquitina-Proteína Ligasas , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transactivadores/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
The anti-Markovnikov hydroamination reaction is considered to be a particular challenge, and one of the reactants, parent hydrazine, is also regarded as a troubling reagent. In this study, we first studied the hydrohydrazination of parent hydrazine via an effective and green catalyst-external electric field (EEF). The calculation results demonstrated that the anti-Markovnikov and Markovnikov pathways are competitive when there was no catalyst. EEF oriented along the negative direction of the X axis (F x ) accelerated the anti-Markovnikov addition reaction. Moreover, it lowered the barrier height of the first step by 16.0 kcal mol-1 (from 27.8 to 11.8 kcal mol-1) when the field strength was 180 (×10-4) au. Under the same conditions, the Markovnikov reaction pathway was inhibited, which means that EEF achieved the specificity of hydrohydrazination. The solvents are favorable for the first step addition reaction, particularly the synergy between solvents and F x lowered the barrier heights by 8.3 (C6H6) and 10.7 (DMSO) kcal mol-1 for an F x = -60 (×10-4) au. Besides, the introduction of the electron-withdrawing substituent (trifluoromethyl) is also a good strategy to catalyze hydrohydrazination, while the electron-donating group (methoxy) is unfavorable.
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SCOPE: Low circulating 25-hydroxyvitamin D (25(OH)D) levels associate with obesity, diabetes, and hyperlipidemia, but the underlying mechanisms remain uncertain. As energy-dense diet contributes to these disorders, this study investigates whether diet could impair vitamin D metabolism. METHODS AND RESULTS: Compared with control chow-fed mice, high fat diet (HFD)-fed mice show lower serum 25(OH)D3 and 1,25(OH)2 D3 levels, lower hepatic vitamin D 25-hydroxylase Cyp2r1 expression but comparable renal vitamin D metabolic enzymes expression. Time course studies show that after HFD feeding, the serum concentrations of cholesterol, triglycerides, fatty acids, glucose, and insulin elevate sequentially and before the reduction of hepatic Cyp2r1 expression and serum 25(OH)D3 levels. Hepatic Cyp2r1 expression also reduces after consuming high fat and high sucrose diet. After high cholesterol diet feeding, serum total cholesterol rises and hepatic Cyp2r1 expression decreases ahead of the reduction of serum 25(OH)D3 . In vitro studies demonstrate that high concentrations of cholesterol, glucose, and insulin significantly inhibit Cyp2r1expression in primary murine hepatocytes. Further studies show that dietary restriction in HFD-fed mice ameliorates hypercholesterolemia, hyperglycemia, and hypertriglyceridemia, and elevates hepatic Cyp2r1 expression and serum 25(OH)D3 level. CONCLUSION: These findings suggest that diet-induced elevation of circulating cholesterol, glucose, and insulin reduces serum 25(OH)D3 level through suppressing hepatic Cyp2r1 expression.
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Hipercolesterolemia , Insulinas , Animales , Calcifediol , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/metabolismo , Colesterol , Sistema Enzimático del Citocromo P-450 , Dieta Alta en Grasa/efectos adversos , Glucosa , Ratones , Vitamina D/análogos & derivadosRESUMEN
BACKGROUND AND OBJECTIVE: soy protein and soy isoflavones have been suggested to be associated with improved cardiovascular risk factors (e.g., lipid profiles and uric acid (UA)), but few studies have been conducted among women with impaired glucose regulation (IGR). This study is aimed to evaluate the effect of isolated daidzein and genistein on lipid profiles, high sensitive C-reactive protein (hs-CRP), and uric acid (UA) among Chinese women with IGR. METHODS AND RESULTS: this randomized, double-blind, and placebo-controlled trial was conducted in 165 Chinese women aged 30-70 years with IGR. Participants were randomly assigned to one of the three groups: 0 mg of daidzein and genistein with 10 g soy protein (placebo group), 50 mg of daidzein with 10 g soy protein (daidzein group), or 50 mg of genistein with 10 g soy protein (genistein group) supplementation for 24 weeks. Fasting serum total cholesterol (TC), triacylglycerol (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), lipoprotein a (LP (a)), hs-CRP, and UA were assessed at baseline, 12, and 24 weeks after intervention. The results showed no significant differences in the changes (%) of TC, TG, HDL-C, LDL-C, LP (a), hs-CRP, and UA between the three treatment groups at weeks 12 or 24 (all P > 0.05). CONCLUSION: neither isolated daidzein nor genistein had a significant effect on cardiovascular health in Chinese women with IGR.
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Enfermedades Cardiovasculares/metabolismo , Genisteína/administración & dosificación , Glucosa/metabolismo , Isoflavonas/administración & dosificación , Adulto , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
Chemotherapy is widely used in a variety of solid tumors, such as lung cancer, gastric cancer and breast cancer. The genotoxic drugs, such as cisplatin, suppress cancer progression either by inhibition cell proliferation or facilitating apoptosis. However, the chemotherapy resistance remains an urgent challenge in cancer therapy, especially in advanced stages. Several studies showed that the activation of pro-survival pathways, such as PI3K-AKT, participated in mediating chemotherapy resistance. The insights into the molecular mechanisms for underlying chemotherapy resistance are of great importance to improve cancer patient survival in advanced stages. The HOIP protein belongs to the RING family E3 ubiquitin ligases and modulates several atypical ubiquitination processes in cellular signaling. Previous studies showed that HOIP might be an important effector in modulating cancer cell death under genotoxic drugs. Here, we report that HOIP associates with PTEN and facilitates PTEN degradation in cancer cells. Depletion of HOIP causes cell cycle arrest and apoptosis, which effects could be rescued by PTEN silencing. Besides, the survival data from public available database show that HOIP expression correlates with poor survival in several types of chemotherapy-treated cancer patients. In conclusion, our study establishes a novel mechanism by which HOIP modulates PTEN stability and facilitates chemotherapy resistance in malignancies.
RESUMEN
OBJECTIVE: The estimation of dietary intake in population-based studies is often assessed by the FFQ. The objective of our study is to evaluate the validity of an FFQ used to assess dietary fatty acid intake among middle-aged Chinese adults in Southern China. DESIGN: The method of triads was applied to obtain the validity coefficients (VC) of the FFQ for specific fatty acids. A subsample was randomly selected from an earlier cross-sectional study. The FFQ and 3d dietary records were used for dietary assessment, and the fatty acid composition of erythrocyte membranes was determined as the biomarker. RESULTS: The Spearman correlation coefficients between the FFQ and 3d dietary records were moderate to good (r = 0.28-0.66). The VC of the FFQ estimated by the method of triads were 0.72, 0.61, 0.65, 0.75 and 0.67 for MUFA, total n-6 fatty acids, alpha-linolenic acid, EPA and DHA, respectively. The VC could not be calculated for SFA, PUFA and total n-3 fatty acids because of negative correlations among the three measurements. But, the correlations between the FFQ and the dietary records were moderate for these fatty acids. CONCLUSIONS: Our FFQ applied in Southern Chinese adults was valid to estimate their dietary fatty acid intake and was thus suitable for use in a large cohort study.