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ABSTRACT: A 54-year-old woman with a history of end-stage renal disease was found to have infiltrative cardiomyopathy by echocardiography. 99mTc-pyrophosphate (99mTc-PYP) scintigraphy was positive with a remarkable myocardial uptake. Gene test found a mutation of AGXT, confirming a final diagnosis of primary hyperoxaluria. Radiotracer uptake was due to high myocardial oxalate deposition. This case illustrates false positivity of the 99mTc-PYP scan caused by hyperoxaluria-associated cardiomyopathy, which raises awareness for other conditions apart from amyloid cardiomyopathy.
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In this study, we explored the changes in plant community diversity and their relationship with soil factors under shrub encroachment pressure by selecting four marsh areas in Sanjiang Plain with different degrees of shrub cover (a, 0≤a≤100%), including marsh with no shrub encroachment (a=0), light shrub encroachment (0
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Biodiversidad
, Suelo
, Humedales
, China
, Suelo/química
, Dinámica Poblacional
, Poaceae/crecimiento & desarrollo
, Plantas/clasificación
, Desarrollo de la Planta
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Ribosome biogenesis is essential for cell growth, proliferation, and animal development. Its deregulation leads to various human disorders such as ribosomopathies and cancer. Thus, tight regulation of ribosome biogenesis is crucial for normal cell homeostasis. Emerging evidence suggests that posttranslational modifications such as ubiquitination and SUMOylation play a crucial role in regulating ribosome biogenesis. Our recent studies reveal that USP36, a nucleolar deubiquitinating enzyme (DUB), acts also as a SUMO ligase to regulate nucleolar protein group SUMOylation, thereby being essential for ribosome biogenesis. Here, we provide an overview of the current understanding of the SUMOylation regulation of ribosome biogenesis and discuss the role of USP36 in nucleolar SUMOylation.
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Dissolved organic carbon (DOC) plays a crucial role in the assessment of greenhouse gas emission and carbon balance in peatlands. However, limited research has been conducted on the seasonal variations and properties of soil water DOC content at different depths in the permafrost peatlands of the Great Hing'an Mountains. In this study, we analyzed the seasonal patterns of soil water DOC contents (surface, 10 cm, 20 cm, 30 cm, 40 cm, and permafrost layer) the permafrost peatlands of the Great Hing'an Mountains (Tuqiang Forestry Bureau), and investigated the influencing factors, such as electrical conductivity, dissolved oxygen, HCO3- concentration, pH value, oxidation-reduction potential, and CO2 content. The stability of DOC was assessed by using UV-Vis spectrum. There were significant seasonal dynamics of DOC content in soil water, with higher contents in autumn and lower content in summer, ranging from 55.7 to 188.1 mg·L-1. There were significant differences in DOC content among different soil depths, with the highest levels detected in the permafrost layer. The DOC content showed a significantly positive correlation with pH value and electrical conductivity, while showed a significantly negative correlation with redox potential, HCO3- concentration, and dissolved oxygen content. Additionally, there was a significantly positive correlation between DOC and CO2 contents. The dissolved CO2 content in soil water increased with soil depth, with the highest content observed in the permafrost layer. Results of spectral analysis showed higher aromaticity in autumn compared to summer, indicating greater stability of DOC during the autumn season. Our results clarified the seasonal variations of soil water DOC in permafrost peatlands of the Great Hing'an Mountains and could provide important data to understand the carbon cycling in the region.
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Hielos Perennes , Suelo , Suelo/química , Estaciones del Año , Hielos Perennes/química , Materia Orgánica Disuelta , Agua/análisis , Dióxido de Carbono/análisis , Carbono/análisis , OxígenoRESUMEN
To understand the variations in greenhouse gas fluxes during the process of returning cropland to wetland in the Sanjiang Plain, we selected naturally restored wetlands of 4, 7, 11, 16 and 20 years as research objects to compare with a cultivated site (soybean plantation for 13 years) and an uncultivated marsh dominated by Deyeuxia purpurea and Carex schmidtii. We measured carbon dioxide (CO2) and methane (CH4) fluxes using a static chamber-gas chromatography and explored the main influencing factors. The results showed that there were seasonal variations in growing-season CO2 and CH4 fluxes of the restored wetlands, with the seasonal trends in greenhouse gases becoming gradually similar to that of natural marsh with increasing restoration time. The mean growing-season CO2 fluxes increased during the early stage of restoration, but then decreased during the late stage, which decreased from 893.4 mg·m-2·h-1 to 494.0 mg·m-2·h-1 in the 4-year and 20-year sites, respectively. Mean CH4 fluxes increased with restoration time, ranging from a weak CH4 sink (soybean fields, -0.6 mg·m-2·h-1) to a CH4 source of 87.8 mg·m-2·h-1(20-year restored site). The CH4 fluxes of experimental plots were consistently lower than that of natural marsh (96.4 mg·m-2·h-1). Increases in water level and soil conductivity resulting from restoration were the main driving factors for the decrease in CO2 fluxes. The increases in water level and soil dissolved organic carbon resulting from restoration were the primary drivers for the increase of CH4 fluxes in the restored wetlands. The global warming potentials increased with restoration time, ranging from 27.8 t·CO2-eq·hm-2(soybean fields) to 130.8 t·CO2-eq·hm-2(plot of 20-year restoration), which gradually approached that of natural marsh (156.3 t·CO2-eq·hm-2). The emission of GHGs from restored wetlands in the Sanjiang Plain gradually approached those of natural marsh. Further monitoring is required to identify the maturity of restored wetlands for achieving greenhouse gas emissions equivalent to that of natural marshland.
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Gases de Efecto Invernadero , Humedales , Dióxido de Carbono , China , Suelo , Glycine max , AguaRESUMEN
Hepatic macrophages represent a key cellular component of the liver and are essential for the progression of acute liver failure (ALF). We construct artificial apoptotic cells loaded with itaconic acid (AI-Cells), wherein the compositions of the synthetic plasma membrane and surface topology are rationally engineered. AI-Cells are predominantly localized to the liver and further transport to hepatic macrophages. Intravenous administration of AI-Cells modulates macrophage inflammation to protect the liver from acetaminophen-induced ALF. Mechanistically, AI-Cells act on caspase-1 to suppress NLRP3 inflammasome-mediated cleavage of pro-IL-1ß into its active form in macrophages. Notably, AI-Cells specifically induce anti-inflammatory memory-like hepatic macrophages in ALF mice, which prevent constitutive overproduction of IL-1ß when liver reinjury occurs. In light of AI-Cells' precise delivery and training of memory-like hepatic macrophages, they offer promising therapeutic potential in reversing ALF by finely controlling inflammatory responses and orchestrating liver homeostasis, which potentially affect the treatment of various types of liver failure.
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Células Artificiales , Fallo Hepático Agudo , Lesiones de Repetición , Animales , Ratones , Lesiones de Repetición/metabolismo , Macrófagos/metabolismo , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/tratamiento farmacológico , Fallo Hepático Agudo/prevención & control , Antiinflamatorios/efectos adversosRESUMEN
The RNA exosome is an essential 3' to 5' exoribonuclease complex that mediates degradation, processing and quality control of virtually all eukaryotic RNAs. The nucleolar RNA exosome, consisting of a nine-subunit core and a distributive 3' to 5' exonuclease EXOSC10, plays a critical role in processing and degrading nucleolar RNAs, including pre-rRNA. However, how the RNA exosome is regulated in the nucleolus is poorly understood. Here, we report that the nucleolar ubiquitin-specific protease USP36 is a novel regulator of the nucleolar RNA exosome. USP36 binds to the RNA exosome through direct interaction with EXOSC10 in the nucleolus. Interestingly, USP36 does not significantly regulate the levels of EXOSC10 and other tested exosome subunits. Instead, it mediates EXOSC10 SUMOylation at lysine (K) 583. Mutating K583 impaired the binding of EXOSC10 to pre-rRNAs, and the K583R mutant failed to rescue the defects in rRNA processing and cell growth inhibition caused by knockdown of endogenous EXOSC10. Furthermore, EXOSC10 SUMOylation is markedly reduced in cells in response to perturbation of ribosomal biogenesis. Together, these results suggest that USP36 acts as a SUMO ligase to promote EXOSC10 SUMOylation critical for the RNA exosome function in ribosome biogenesis.
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Exorribonucleasas , Complejo Multienzimático de Ribonucleasas del Exosoma , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Exorribonucleasas/genética , Exorribonucleasas/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , ARN/metabolismo , Precursores del ARN/genética , Precursores del ARN/metabolismo , Procesamiento Postranscripcional del ARN , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Humanos , Línea CelularRESUMEN
miRNA biogenesis is a cellular process that produces mature miRNAs from their primary transcripts, pri-miRNAs, via two RNAse III enzyme complexes: the Drosha-DGCR8 microprocessor complex in the nucleus and the Dicer-TRBP complex in the cytoplasm. Emerging evidence suggests that miRNA biogenesis is tightly regulated by posttranscriptional and posttranslational modifications and aberrant miRNA biogenesis is associated with various human diseases including cancer. DGCR8 has been shown to be modified by SUMOylation. Yet, the SUMO ligase mediating DGCR8 SUMOylation is currently unknown. Here, we report that USP36, a nucleolar ubiquitin-specific protease essential for ribosome biogenesis, is a novel regulator of DGCR8. USP36 interacts with the microprocessor complex and promotes DGCR8 SUMOylation, specifically modified by SUMO2. USP36-mediated SUMOylation does not affect the levels of DGCR8 and the formation of the Drosha-DGCR8 complex, but promotes the binding of DGCR8 to pri-miRNAs. Consistently, abolishing DGCR8 SUMOylation significantly attenuates its binding to pri-miRNAs and knockdown of USP36 attenuates pri-miRNA processing, resulting in marked reduction of tested mature miRNAs. Induced expression of a SUMOylation-defective mutant of DGCR8 inhibits cell proliferation. Together, these results suggest that USP36 plays an important role in regulating miRNA biogenesis by SUMOylating DGCR8. Significance: This study identifies that USP36 mediates DGCR8 SUMOylation by SUMO2 and is critical for miRNA biogenesis. As USP36 is frequently overexpressed in various human cancers, our study suggests that deregulated USP36-miRNA biogenesis pathway may contribute to tumorigenesis.
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MicroARNs , Neoplasias , Humanos , MicroARNs/genética , Proteínas de Unión al ARN/genética , Procesamiento Postranscripcional del ARN , Carcinogénesis/genética , Neoplasias/genética , Microcomputadores , Ubiquitina Tiolesterasa/genéticaRESUMEN
Deregulated MYC overexpression and activation contributes to tumor growth and progression. Given the short half-life and unstable nature of the MYC protein, it is not surprising that the oncoprotein is highly regulated via diverse posttranslational mechanisms. Among them, ubiquitination dynamically controls the levels and activity of MYC during normal cell growth and homeostasis, whereas the disturbance of the ubiquitination/deubiquitination balance enables unwanted MYC stabilization and activation. In addition, MYC is also regulated by SUMOylation which crosstalks with the ubiquitination pathway and controls MYC protein stability and activity. In this mini-review, we will summarize current updates regarding MYC ubiquitination and provide perspectives about these MYC regulators as potential therapeutic targets in cancer.
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Detection of post-translational modifications in c-Myc is an invaluable tool in assessing Myc status, particularly in cancer. However, it can be challenging to detect these modifications. The evaluation of phosphorylation status of c-Myc can also be challenging with the current commercially available phosphorylation sensitive antibodies. Here, we describe protocols for the immunoprecipitation of endogenous c-Myc to probe for phosphorylation status, as well as the detection of ubiquitination and SUMOylation on c-Myc. We will also discuss the challenges of detecting phosphorylated c-Myc in formalin-fixed paraffin-embedded tissues by immunofluorescence and describe a protocol using a new rat monoclonal antibody we have generated suitable for this purpose.
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Inmunoprecipitación/métodos , Procesamiento Proteico-Postraduccional/genética , Proteínas Proto-Oncogénicas c-myc/genética , Técnica del Anticuerpo Fluorescente , Genes myc/genética , Genes myc/fisiología , Humanos , Fosforilación , Procesamiento Proteico-Postraduccional/fisiología , Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Sumoilación , UbiquitinaciónRESUMEN
SUMOylation plays a crucial role in regulating diverse cellular processes including ribosome biogenesis. Proteomic analyses and experimental evidence showed that a number of nucleolar proteins involved in ribosome biogenesis are modified by SUMO. However, how these proteins are SUMOylated in cells is less understood. Here, we report that USP36, a nucleolar deubiquitinating enzyme (DUB), promotes nucleolar SUMOylation. Overexpression of USP36 enhances nucleolar SUMOylation, whereas its knockdown or genetic deletion reduces the levels of SUMOylation. USP36 interacts with SUMO2 and Ubc9 and directly mediates SUMOylation in cells and in vitro. We show that USP36 promotes the SUMOylation of the small nucleolar ribonucleoprotein (snoRNP) components Nop58 and Nhp2 in cells and in vitro and their binding to snoRNAs. It also promotes the SUMOylation of snoRNP components Nop56 and DKC1. Functionally, we show that knockdown of USP36 markedly impairs rRNA processing and translation. Thus, USP36 promotes snoRNP group SUMOylation and is critical for ribosome biogenesis and protein translation.
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Ribonucleoproteínas Nucleolares Pequeñas , Sumoilación , Proteínas de Ciclo Celular/metabolismo , Enzimas Desubicuitinizantes/genética , Células HeLa , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteómica , Ribonucleoproteínas Nucleolares Pequeñas/genética , Ribonucleoproteínas Nucleolares Pequeñas/metabolismo , Ribosomas/genética , Ribosomas/metabolismo , Ubiquitina Tiolesterasa/genéticaRESUMEN
BACKGROUND: A low appropriate therapy rate indicates that a minority of patients will benefit from their implantable cardioverter defibrillator (ICD). Quantitative measurements from 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) may predict ventricular arrhythmia (VA) occurrence after ICD placement. METHODS: We performed a prospective observational study and recruited patients who required ICD placement. Pre-procedure image scans were performed. Patients were followed up for VA occurrence. Associations between image results and VA were analyzed. RESULTS: In 51 patients (33 males, 53.9 ± 17.2 years) analyzed, 17 (33.3%) developed VA. Compared with patients without VA, patients with VA had significantly larger values in scar area (17.7 ± 12.4% vs. 7.0 ± 7.9%), phase standard deviation (51.4° ± 14.0° vs. 34.0° ± 15.0°), bandwidth (172.9° ± 39.8° vs. 128.7° ± 49.9°), sum thickening score (STS, 29.5 ± 11.1 vs. 17.8 ± 13.2), and sum motion score (42.9 ± 11.5 vs. 33.0 ± 19.0). Cox regression analysis and receiver operating characteristic curve analysis showed that scar size, dyssynchrony, and STS were associated with VA occurrence (HR, 4.956, 95% CI 1.70-14.46). CONCLUSION: Larger left ventricular scar burden, increased dyssynchrony, and higher STS quantified by 18F-FDG PET may indicate a higher VA incidence after ICD placement.
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Técnicas de Imagen Cardíaca/métodos , Desfibriladores Implantables/efectos adversos , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Taquicardia Ventricular/etiología , Fibrilación Ventricular/etiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Reproducibilidad de los Resultados , Tomografía Computarizada de Emisión de Fotón Único , Función Ventricular IzquierdaRESUMEN
PURPOSE: 18F-FDG PET myocardial metabolic imaging is used to estimate myocardial viability. However, poor image quality can affect the accurate quantification of viable myocardium. We assessed the feasibility of a rescue protocol that reinjected low-dose 18F-FDG with simultaneous 1 to 2 U of insulin injection and oral administration of 10 g of glucose to improve the image quality of 18F-FDG PET myocardial metabolic imaging. PATIENTS AND METHODS: Fifty-one consecutive patients with poor quality to uninterpretable 18F-FDG PET/CT myocardial metabolic images received the rescue protocol immediately after the initial image acquisition. The postrescue image acquisition was performed 1 hour later. The rescue image quality was compared with the initial image. The qualitative visual estimation of the images was graded as follows: grade 0, homogeneous, minimal uptake; grade 1, predominantly minimal or mild uptake; grade 2, moderate uptake; and grade 3, good uptake. The myocardium-to-blood pool activity ratio (M/B) was measured to assess the image quality quantitatively. RESULTS: The grades of 0 to 3 were observed in 24 (47%), 27 (53%), 0 (0%), and 0 (0%) patients, respectively, for the initial imaging, and in 0 (0%), 3 (5.9%), 4 (7.8%), and 44 (86.3%) patients for the rescue imaging (P < 0.001). The rescue M/B was significantly higher than the initial M/B (3.4 ± 1.4 vs 1.6 ± 0.6, respectively; P < 0.001). CONCLUSIONS: The rescue protocol successfully and rapidly improved the quality of myocardial 18F-FDG metabolic imaging.
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Fluorodesoxiglucosa F18 , Corazón/diagnóstico por imagen , Miocardio/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Control de CalidadRESUMEN
BACKGROUND: This study aimed to compare the accuracy of gated-SPECT (GSPECT) and gated-PET (GPET) in the assessment of left ventricular (LV) end-diastolic volumes (EDVs), end-systolic volumes (ESVs) and LV ejection fractions (LVEFs) among patients with prior myocardial infarction (MI). METHODS: One hundred and sixty-eight consecutive patients with MI who underwent GSPECT and GPET were included. Of them, 76 patients underwent CMR in addition to the two imaging modalities. The measurements of LV volumes and LVEF were performed using Quantitative Gated SPECT (QGS), Emory Cardiac Toolbox (ECTB), and 4D-MSPECT (4DM). RESULTS: The correlation between GPET, GSPECT, and CMR were excellent for LV EDV (r = 0.855 to 0.914), ESV (r = 0.852 to 0.949), and LVEF (r = 0.618 to 0.820), as calculated from QGS, ECTB, and 4DM. In addition, subgroup analysis revealed that EDV, ESV, and LVEF measured by GPET were accurate in patients with different extents of total perfusion defect (TPD), viable myocardium, and perfusion/metabolic mismatch. Furthermore, multivariate regression analysis identified that mismatch score was associated with the difference in EDV (P < 0.05) measurements between GPET and CMR. CONCLUSIONS: In patients with MI, LV volumes and LVEF scores measured by both GSPECT and GPET imaging were comparable to those determined by CMR, but should not be interchangeable in individual patients.
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Fluorodesoxiglucosa F18 , Imagen de Acumulación Sanguínea de Compuerta/métodos , Infarto del Miocardio/fisiopatología , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Tecnecio Tc 99m Sestamibi , Tomografía Computarizada de Emisión de Fotón Único/métodos , Función Ventricular Izquierda , Anciano , Volumen Cardíaco/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagen , Volumen Sistólico/fisiologíaRESUMEN
The stability and activity of the p53 tumor suppressor protein are tightly regulated by various posttranslational modifications, including SUMOylation. p53 can be modified by both SUMO1 and SUMO2, although how SUMOylation regulates p53 activity is still obscure. Whether p53 activity is directly regulated by deSUMOylation is also unclear. Here, we show that SENP1, a SUMO-specific protease implicated in pro-oncogenic roles, is a p53 deSUMOylating enzyme. SENP1 interacts with p53 and deSUMOylates p53 in cells and in vitro. Knockdown of SENP1 markedly induced p53 transactivation activity. We further show that SENP1 depletion synergizes with DNA damage-inducing agent etoposide to induce p53 activation and the expression of p21, leading to synergistic growth inhibition of cancer cells. Our results reveal that SENP1 is a critical p53 deSUMOylating enzyme and a promising therapeutic target in wild-type p53 containing cancer cells.
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Cisteína Endopeptidasas/metabolismo , Proteína SUMO-1/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Cisteína Endopeptidasas/genética , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Etopósido/farmacología , Humanos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Procesamiento Proteico-Postraduccional/genética , Proteína SUMO-1/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
OBJECTIVE: To assess the benefits of coronary collateral circulation on myocardial perfusion, viability and function in patients with total occlusion of a single coronary artery using the 99mTc-sestamibi SPECT and 18F-fluorodeoxyglucose PET. METHODS: 164 Consecutive patients were included who underwent coronary angiography results exhibited total occlusion of a single coronary artery and received 99mTc-MIBI SPECT and 18F-FDG PET within 90 days of angiography. Myocardial perfusion and viability in patients with collateral circulation and those without it were compared. Long-term follow-up was performed through a review of patient clinical records. RESULTS: Collateral circulation was present in 56 patients (34%) and absent in 108 patients (66%). The total perfusion defect size in patients with collateral circulation decreased when compared to those without (30% ± 13% to 35% ± 14%, P < .05). The myocardial viability was 22% ± 12% in patients with collateral circulation, and 12% ± 9% in those without (P < .001). The left ventricular ejection fraction was higher, and the end-diastolic and end-systolic left ventricular volumes were lower in patients with collateral circulation (39% ± 11%, 138 ± 66, 89 ± 57) compared to patients without collateral circulation (31% ± 9%, 177 ± 55, 125 ± 48, all P < .001, respectively). Multi-factor logistic regression identified that concerning the variables of sex, age, viable myocardium, collateral circulation, treatment type and others, only treatment type was significantly associated with therapeutic effects (OR 3.872, 95% CI 1.915-7.830, P < .001). CONCLUSION: Collateral circulation can preserve resting myocardial blood perfusion and myocardial viability, and help maintain the function of the left ventricular myocardium. The appropriate treatment strategy will have a substantial impact on the therapeutic outcome.
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Circulación Colateral , Circulación Coronaria , Oclusión Coronaria/fisiopatología , Fluorodesoxiglucosa F18 , Radiofármacos , Tecnecio Tc 99m Sestamibi , Tomografía Computarizada de Emisión de Fotón Único/métodos , Anciano , Femenino , Corazón/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Supervivencia TisularRESUMEN
The transcription factor c-MYC (MYC thereafter) is a global regulator of gene expression. It is overexpressed or deregulated in human cancers of diverse origins and plays a key role in the development of cancers. Hypoxia-inducible factors (HIFs), a central regulator for cells to adapt to low cellular oxygen levels, is also often overexpressed and activated in many human cancers. HIF mediates the primary transcriptional response of a wide range of genes in response to hypoxia. Earlier studies focused on the inhibition of MYC by HIF during hypoxia, when MYC is expressed at physiological level, to help cells survive under low oxygen conditions. Emerging evidence suggests that MYC and HIF also cooperate to promote cancer cell growth and progression. This review will summarize the current understanding of the complex molecular interplay between MYC and HIF.
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Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson's disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.
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Neoplasias de la Mama/enzimología , Neoplasias Pulmonares/enzimología , Proteínas de Neoplasias/metabolismo , Fosfoglicerato-Deshidrogenasa/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Células A549 , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Desnudos , Proteínas de Neoplasias/genética , Fosfoglicerato-Deshidrogenasa/genética , Serina/genética , Serina/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in HER2+ disease, examining the relationship between HER2 expression and MYC phosphorylation in HER2+ patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC;NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC;NeuNT tumors match existing subtypes of amplified-HER2, estrogen receptor-negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR-targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers.
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Regulación Neoplásica de la Expresión Génica , Neoplasias Mamarias Experimentales/metabolismo , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Receptor ErbB-2/metabolismo , Animales , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Receptor ErbB-2/genéticaRESUMEN
The transcription factor c-MYC (MYC thereafter) controls diverse transcription programs and plays a key role in the development of many human cancers. Cells develop multiple mechanisms to ensure that MYC levels and activity are precisely controlled in normal physiological context. As a short half-lived protein, MYC protein levels are tightly regulated by the ubiquitin proteasome system. Over a dozen of ubiquitin ligases have been found to ubiquitinate MYC whereas a number of deubiquitinating enzymes counteract this process. Recent studies show that SUMOylation and deSUMOylation can also regulate MYC protein stability and activity. Interestingly, evidence suggests an intriguing crosstalk between MYC ubiquitination and SUMOylation. Deregulation of the MYC ubiquitination-SUMOylation regulatory network may contribute to tumorigenesis. This review is intended to provide the current understanding of the complex regulation of the MYC biology by dynamic ubiquitination and SUMOylation and their crosstalk.