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1.
Nat Commun ; 12(1): 2331, 2021 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-33888710

RESUMEN

During the double fertilization process, pollen tubes deliver two sperm cells to an ovule containing the female gametes. In the pollen tube, the vegetative nucleus and sperm cells move together to the apical region where the vegetative nucleus is thought to play a crucial role in controlling the direction and growth of the pollen tube. Here, we report the generation of pollen tubes in Arabidopsis thaliana whose vegetative nucleus and sperm cells are isolated and sealed by callose plugs in the basal region due to apical transport defects induced by mutations in the WPP domain-interacting tail-anchored proteins (WITs) and sperm cell-specific expression of a dominant mutant of the CALLOSE SYNTHASE 3 protein. Through pollen-tube guidance assays, we show that the physiologically anuclear mutant pollen tubes maintain the ability to grow and enter ovules. Our findings provide insight into the sperm cell delivery mechanism and illustrate the independence of the tip-localized vegetative nucleus from directional growth control of the pollen tube.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiología , Núcleo Celular/metabolismo , Tubo Polínico/crecimiento & desarrollo , Polinización/fisiología , Proteínas de Arabidopsis/genética , Movimiento Celular/fisiología , Fertilización/fisiología , Glucanos/metabolismo , Glucosiltransferasas/genética , Glucosiltransferasas/metabolismo , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Óvulo Vegetal/metabolismo , Plantas Modificadas Genéticamente , Tubo Polínico/citología , Tubo Polínico/metabolismo
2.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803178

RESUMEN

Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.


Asunto(s)
Proteínas Portadoras/metabolismo , Síndrome Metabólico , Neoplasias , Enfermedades del Sistema Nervioso , Proteínas Supresoras de Tumor/metabolismo , Animales , Humanos , Inflamación/metabolismo , Inflamación/patología , Inflamación/terapia , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Síndrome Metabólico/terapia , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapia , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/terapia , Proteínas Nucleares/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Similares a la Proteína de Unión a TATA-Box/metabolismo , Tiorredoxinas/metabolismo
3.
Int J Mol Sci ; 22(5)2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33804586

RESUMEN

The nucleoli are membrane-less nuclear substructures that govern ribosome biogenesis and participate in multiple other cellular processes such as cell cycle progression, stress sensing, and DNA damage response. The proper functioning of these organelles is ensured by specific proteins that maintain nucleolar structure and mediate key nucleolar activities. Among all nucleolar proteins, treacle encoded by TCOF1 gene emerges as one of the most crucial regulators of cellular processes. TCOF1 was initially discovered as a gene involved in the Treacher Collins syndrome, a rare genetic disorder characterized by severe craniofacial deformations. Later studies revealed that treacle regulates ribosome biogenesis, mitosis, proliferation, DNA damage response, and apoptosis. Importantly, several reports indicate that treacle is also involved in cancer development, progression, and response to therapies, and may contribute to other pathologies such as Hirschsprung disease. In this manuscript, we comprehensively review the structure, function, and the regulation of TCOF1/treacle in physiological and pathological processes.


Asunto(s)
Nucléolo Celular/metabolismo , Homeostasis , Disostosis Mandibulofacial/fisiopatología , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Nucléolo Celular/genética , Humanos , Proteínas Nucleares/genética , Fosfoproteínas/genética
4.
Nat Genet ; 53(4): 477-486, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33795867

RESUMEN

Acquisition of cell fate is thought to rely on the specific interaction of remote cis-regulatory modules (CRMs), for example, enhancers and target promoters. However, the precise interplay between chromatin structure and gene expression is still unclear, particularly within multicellular developing organisms. In the present study, we employ Hi-M, a single-cell spatial genomics approach, to detect CRM-promoter looping interactions within topologically associating domains (TADs) during early Drosophila development. By comparing cis-regulatory loops in alternate cell types, we show that physical proximity does not necessarily instruct transcriptional states. Moreover, multi-way analyses reveal that multiple CRMs spatially coalesce to form hubs. Loops and CRM hubs are established early during development, before the emergence of TADs. Moreover, CRM hubs are formed, in part, via the action of the pioneer transcription factor Zelda and precede transcriptional activation. Our approach provides insight into the role of CRM-promoter interactions in defining transcriptional states, as well as distinct cell types.


Asunto(s)
Linaje de la Célula/genética , Cromatina/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas Nucleares/genética , Factores de Transcripción/genética , Animales , Diferenciación Celular , Cromatina/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citología , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Embrión no Mamífero , Elementos de Facilitación Genéticos , Perfilación de la Expresión Génica , Genómica , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , Análisis de la Célula Individual , Factores de Transcripción/clasificación , Factores de Transcripción/metabolismo , Transcripción Genética
5.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809261

RESUMEN

Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.


Asunto(s)
Anemia Diseritropoyética Congénita/genética , Síndromes de Inmunodeficiencia/genética , Inflamación/genética , Quinasas Quinasa Quinasa PAM/genética , Factores de Transcripción NFATC/genética , Proteínas Nucleares/genética , Osteomielitis/genética , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Anemia Diseritropoyética Congénita/metabolismo , Anemia Diseritropoyética Congénita/patología , Animales , Resorción Ósea/genética , Resorción Ósea/metabolismo , Resorción Ósea/patología , Diferenciación Celular/genética , Humanos , Síndromes de Inmunodeficiencia/metabolismo , Síndromes de Inmunodeficiencia/patología , Inflamación/metabolismo , Inflamación/patología , Lipopolisacáridos/genética , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Noqueados , FN-kappa B/genética , Proteínas Nucleares/deficiencia , Proteínas Nucleares/metabolismo , Osteoclastos/metabolismo , Osteogénesis/genética , Osteomielitis/metabolismo , Osteomielitis/patología , Ligando RANK/genética , Transducción de Señal/genética , Factor de Transcripción ReIA/genética
6.
Science ; 372(6538): 150-156, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33833117

RESUMEN

In most vertebrates, camera-style eyes contain retinal ganglion cell neurons that project to visual centers on both sides of the brain. However, in fish, ganglion cells were thought to innervate only the contralateral side, suggesting that bilateral visual projections appeared in tetrapods. Here we show that bilateral visual projections exist in non-teleost fishes and that the appearance of ipsilateral projections does not correlate with terrestrial transition or predatory behavior. We also report that the developmental program that specifies visual system laterality differs between fishes and mammals, as the Zic2 transcription factor, which specifies ipsilateral retinal ganglion cells in tetrapods, appears to be absent from fish ganglion cells. However, overexpression of human ZIC2 induces ipsilateral visual projections in zebrafish. Therefore, the existence of bilateral visual projections likely preceded the emergence of binocular vision in tetrapods.


Asunto(s)
Evolución Biológica , Encéfalo/anatomía & histología , Peces/anatomía & histología , Peces/genética , Células Ganglionares de la Retina/citología , Vías Visuales , Animales , Diferenciación Celular , Ojo/anatomía & histología , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Peces/metabolismo , Lateralidad Funcional , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Retina/embriología , Retina/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Visión Binocular , Pez Cebra/anatomía & histología , Pez Cebra/genética
7.
J Environ Pathol Toxicol Oncol ; 40(2): 89-98, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33822520

RESUMEN

AIM: In our study, a new grading model (e-GM) including nuclear membrane irregularity highlighted by emerin expression was proposed for renal cell carcinomas (RCC). It was aimed to investigate the relationship of this model with WHO/ISUP grading system, histopathological features, and prognosis. METHODS AND RESULTS: 86 RCC cases were included in the study. The mean age of the patients was 59.65, and the mean tumor size was 6.36 cm. According to pTNM staging, 45 of the cases were stage 1, 11 were stage 2, 26 were stage 3, and 4 were stage 4. According to e-GM grading, advanced tumor grade was found to be associated with perirenal tissue extension, necrosis, lymphovascular invasion, distant metastasis, advanced pT and TNM stage. Nuclear membrane irregularity caused an increase in tumor grade in 17 wi-GS grade 1 cases, 14 WHO/ISUP grading system (wi-GS) grade 2 cases, and 1 wi-GS grade 3 case. In the stepwise statistical analysis, it was determined that the most important prognostic factor was the TNM stage, followed by age and tumor size. CONCLUSIONS: Statistical analyses showed that nuclear membrane irregularity should be a criterion for classification according to e-GM in wi-grade 2 cases, but not necessarily in wi-grade 1 cases. Nuclear membrane irregularity was a prominent feature at high tumor grades, and its expression in RCCs suggests that it may be a target for tumor-specific treatments.


Asunto(s)
Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Análisis de Supervivencia , Carga Tumoral , Organización Mundial de la Salud
8.
Mol Med Rep ; 23(6)2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33864660

RESUMEN

In recent years, increasing evidence has confirmed that exosomal circular RNAs (circRNAs) serve a crucial role in the prognostic prediction and diagnosis of liver cancer (LC). The present study compared the expression patterns of exosomal circRNAs during transarterial chemoembolization (TACE). CircRNA sequencing analysis identified 390 differentially expressed circRNAs between the prior TACE and following the first TACE operation groups and 489 differentially expressed circRNAs between the prior to TACE and following the second TACE operation groups. Gene Ontology analysis of the differentially expressed circRNAs demonstrated that they were associated with fatty acid metabolism, receptor binding and membrane protein complexes. Kyoto Encyclopedia of Genes and Genomes pathway analysis predicted that protein digestion and absorption pathways were activated following TACE. A novel gene was screened out; hsa­circRNA­G004213 (circ­G004213) was significantly upregulated following TACE (fold change >10, P < 0.01). Further analysis found circ­G004213 significantly increased the cisplatin sensitivity of HepG2 cells and positively associated with the prognosis of tumor­bearing mice. Based on the potential downstream miRNAs and mRNAs, the circRNA­miRNA­mRNA network was constructed. It was demonstrated that circ­G004213 regulated cisplatin resistance via the miR­513b­5p/PRPF39 axis. Finally, the present study confirmed that circ­G004213 was positively associated with the prognosis of patients with LC following TACE. Therefore, circ­G004213 may be used as an indicator for predicting the efficacy of TACE.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/genética , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos , Exosomas/genética , Neoplasias Hepáticas/genética , ARN Circular/metabolismo , Adulto , Anciano , Animales , Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Células Cultivadas , Quimioembolización Terapéutica , Cisplatino/administración & dosificación , Exosomas/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , ARN Circular/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
9.
Medicine (Baltimore) ; 100(14): e25278, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832094

RESUMEN

ABSTRACT: A kinase interacting protein 1 (AKIP1) is upregulated in cancer cells/tissues and associated with deteriorative tumor features, while it has not been investigated in tongue squamous cell carcinoma (TSCC). The goal of this study was to measure AKIP1 expression and analyze its correlation with clinical feature and prognosis in TSCC patients.We retrospectively reviewed 194 TSCC patients, whose formalin fixed paraffin-embedded (FFPE) tumor tissue specimens and paired adjacent tissue specimens were accessible for AKIP1 detection by immunohistochemistry (IHC). Whereas only 107 patients whose fresh-frozen tumor tissue and paired fresh-frozen adjacent tissue that were still available in storage were included for AKIP1 mRNA detection by real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR).AKIP1 expression (both the protein detected by IHC and mRNA detected by RT-qPCR) was higher in TSCC tissue than that in adjacent tissue. In addition, both tumor AKIP1 mRNA and protein expressions were correlated with advanced N stage and TNM stage, while they were not correlated with other clinical features in TSCC patients. As for survival, there was a correlation of AKIP1 mRNA with poor overall survival (OS), while the correlation of AKIP1 protein expression with OS was of limited statistical significance.There is an upregulation of AKIP1 in TSCC and it correlates with lymph node metastasis as well as unfavorable prognosis in TSCC patients.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma de Células Escamosas/genética , Proteínas Nucleares/metabolismo , Neoplasias de la Lengua/genética , Regulación hacia Arriba , Adulto , Anciano , Biomarcadores/análisis , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Humanos , Metástasis Linfática/genética , Persona de Mediana Edad , ARN Mensajero/metabolismo , Estudios Retrospectivos , Neoplasias de la Lengua/patología
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(3): 447-452, 2021 Mar 25.
Artículo en Chino | MEDLINE | ID: mdl-33849838

RESUMEN

OBJECTIVE: To investigate the effect of speckle-type POZ protein (SPOP) on proliferation, apoptosis, migration and invasion of renal cell carcinoma (RCC) and explore the potential mechanisms. OBJECTIVE: Renal carcinoma cell lines (786-O, A704, and Caki-2) cultured in vitro were transfected with a SPOP-overexpressing plasmid, and the changes in proliferation of the cells were detected using colony formation and MTT assay; TUNEL assay was used to assess apoptosis of the cells. The changes in migration and invasion abilities of the cells were examined using wound healing assay and Transwell assay. The mRNA and protein levels of SPOP and c-Jun in the transfected cells were measured using real-time PCR and Western blotting. OBJECTIVE: SPOP over-expression obviously promoted the proliferation, migration and invasion of 786-O, A704 and Caki-2 cells (P < 0.05). Compared with the control cells, 786-o and Caki-2 cells over-expressing SPOP exhibited significantly lowered apoptosis rates (P < 0.05). The results of real-time PCR demonstrated that the transfected cells did not show obvious changes in the mRNA level of c-Jun, but the protein expressions of SPOP and c-jun increased significantly as shown by Western blotting (P < 0.05). OBJECTIVE: SPOP can promote proliferation, migration, and invasion and suppress apoptosis of renal carcinoma cells possibly by promoting the expression of c-Jun.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Apoptosis , Carcinoma de Células Renales/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Invasividad Neoplásica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-jun , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
11.
Chimia (Aarau) ; 75(4): 319-322, 2021 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-33902802

RESUMEN

Cellular homeostasis importantly relies on the correct nucleoplasmic distribution of a large number of RNA molecules and proteins, which are shuttled by specialized transport receptors. The nuclear import receptor importin-5, also called IPO5, RanBP5 or karyopherin ß3, mediates the translocation of proteins to the nucleus, and thus regulates critical signaling pathways and cellular functions. The normal function of IPO5 appears to be disrupted in cancer cells due to aberrant overexpression. IPO5 also demonstrated a pivotal role in viral replication. The constant increasing number of publications shows an interest within the scientific community as a therapeutic target due to its pivotal role in protein trafficking.


Asunto(s)
Proteínas Nucleares , beta Carioferinas , Transporte Activo de Núcleo Celular , Núcleo Celular/metabolismo , Carioferinas/metabolismo , Proteínas Nucleares/metabolismo , beta Carioferinas/metabolismo
12.
Nat Commun ; 12(1): 2130, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33837217

RESUMEN

Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria to regulate metabolism. Motivated by an intriguing negative association between mito-SEPs and inflammation, here we screen for mito-SEPs that modify inflammatory outcomes and report a mito-SEP named "Modulator of cytochrome C oxidase during Inflammation" (MOCCI) that is upregulated during inflammation and infection to promote host-protective resolution. MOCCI, a paralog of the NDUFA4 subunit of cytochrome C oxidase (Complex IV), replaces NDUFA4 in Complex IV during inflammation to lower mitochondrial membrane potential and reduce ROS production, leading to cyto-protection and dampened immune response. The MOCCI transcript also generates miR-147b, which targets the NDUFA4 mRNA with similar immune dampening effects as MOCCI, but simultaneously enhances RIG-I/MDA-5-mediated viral immunity. Our work uncovers a dual-component pleiotropic regulation of host inflammation and immunity by MOCCI (C15ORF48) for safeguarding the host during infection and inflammation.


Asunto(s)
Complejo IV de Transporte de Electrones/genética , Pleiotropía Genética/inmunología , Inflamación/inmunología , MicroARNs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Línea Celular , Complejo IV de Transporte de Electrones/metabolismo , Técnicas de Inactivación de Genes , Humanos , Inflamación/genética , Inflamación/patología , Potencial de la Membrana Mitocondrial/inmunología , MicroARNs/genética , Mitocondrias/inmunología , Mitocondrias/patología , Cultivo Primario de Células , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba/inmunología
13.
Mol Cell ; 81(6): 1126-1127, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33740471
14.
Mol Cell ; 81(6): 1128-1129, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33740472

RESUMEN

Huang et al. (2021) identified a mechanism acting through the arginine methyltransferase PRMT6 that stabilizes the interaction of RCC1 with chromatin, promoting cell proliferation and tumorigenicity. Targeting this mechanism might enhance the treatment of tumors such as glioblastoma.


Asunto(s)
Glioblastoma , Proteínas Nucleares , Carcinogénesis/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Cromosomas/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Metilación , Mitosis , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Células Madre/metabolismo
15.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669042

RESUMEN

Since its first identification as a cardiac transverse tubule (t-tubule) protein, followed by the cloning of the cardiac isoform responsible for t-tubule membrane microdomain formation, cardiac bridging integrator 1 (cBIN1) and its organized microdomains have emerged as a key mechanism in maintaining normal beat-to-beat heart contraction and relaxation. The abnormal remodeling of cBIN1-microdomains occurs in stressed and diseased cardiomyocytes, contributing to the pathophysiology of heart failure. Due to the homeostatic turnover of t-tubule cBIN1-microdomains via microvesicle release into the peripheral circulation, plasma cBIN1 can be assayed as a liquid biopsy of cardiomyocyte health. A new blood test cBIN1 score (CS) has been developed as a dimensionless inverse index derived from plasma cBIN1 concentration with a diagnostic and prognostic power for clinical outcomes in stable ambulatory patients with heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Recent evidence further indicates that exogenous cBIN1 introduced by adeno-associated virus 9-based gene therapy can rescue cardiac contraction and relaxation in failing hearts. The therapeutic potential of cBIN1 gene therapy is enormous given its ability to rescue cardiac inotropy and provide lusitropic protection in the meantime. These unprecedented capabilities of cBIN1 gene therapy are shifting the current paradigm of therapy development for heart failure, particularly HFpEF.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/sangre , Terapia Genética/métodos , Insuficiencia Cardíaca/sangre , Miocitos Cardíacos/metabolismo , Proteínas Nucleares/sangre , Retículo Sarcoplasmático/metabolismo , Proteínas Supresoras de Tumor/sangre , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Biomarcadores/sangre , Señalización del Calcio/fisiología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Humanos , Proteínas de la Membrana/metabolismo , Contracción Miocárdica , Miocitos Cardíacos/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Dominios Proteicos , Sarcolema/metabolismo , Retículo Sarcoplasmático/patología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
16.
Nature ; 592(7852): 144-149, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33731927

RESUMEN

The accurate segregation of chromosomes during meiosis-which is critical for genome stability across sexual cycles-relies on homologous recombination initiated by DNA double-strand breaks (DSBs) made by the Spo11 protein1,2. The formation of DSBs is regulated and tied to the elaboration of large-scale chromosome structures3-5, but the protein assemblies that execute and control DNA breakage are poorly understood. Here we address this through the molecular characterization of Saccharomyces cerevisiae RMM (Rec114, Mei4 and Mer2) proteins-essential, conserved components of the DSB machinery2. Each subcomplex of Rec114-Mei4 (a 2:1 heterotrimer) or Mer2 (a coiled-coil-containing homotetramer) is monodispersed in solution, but they independently condense with DNA into reversible nucleoprotein clusters that share properties with phase-separated systems. Multivalent interactions drive this condensation. Mutations that weaken protein-DNA interactions strongly disrupt both condensate formation and DSBs in vivo, and thus these processes are highly correlated. In vitro, condensates fuse into mixed RMM clusters that further recruit Spo11 complexes. Our data show how the DSB machinery self-assembles on chromosome axes to create centres of DSB activity. We propose that multilayered control of Spo11 arises from the recruitment of regulatory components and modulation of the biophysical properties of the condensates.


Asunto(s)
Roturas del ADN de Doble Cadena , ADN de Hongos/metabolismo , Meiosis , Proteínas Nucleares/metabolismo , Nucleoproteínas/metabolismo , Recombinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae , ADN de Hongos/química , Endodesoxirribonucleasas/metabolismo , Recombinación Homóloga , Proteínas Nucleares/química , Nucleoproteínas/química , Unión Proteica , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Recombinasas/química , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química
17.
Gene ; 784: 145584, 2021 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-33753149

RESUMEN

Sister chromatid cohesion (SCC) is essential for the maintenance of genome integrity. The establishment of SCC is coupled to DNA replication, and this is achieved in budding yeast Saccharomyces cerevisiae by a mechanism that is dependent on the interaction between Eco1 acetyltransferase and PCNA in the DNA replication complex. In vertebrates, the Eco1 homolog ESCO2 has been reported to interact with MCM complex in the DNA replication complex to establish DNA replication-dependent cohesion. Here we show that budding yeast Eco1 is also physically interacted with the MCM complex. We found that Eco1 was specifically bound to Mcm2 subunit in the MCM complex and they interacted via their N-terminal regions, using yeast two-hybrid system. The underlying mechanism of the interaction was different between yeast and vertebrates. Intensive molecular dissection of Eco1 identified residues important for interaction with Mcm2 and/or PCNA. Mutant forms of Eco1 (Eco1mWW and Eco1mGRK), where sets of the identified residues were substituted with alanine, resulted in impaired SCC, decreased level of acetylation of Smc3, and a reduction of Eco1 protein amount in yeast cells. We, hence, suggest that Eco1 is stabilized by its interactions with MCM complex and PCNA, which allows it to promote DNA replication-coupled SCC establishment.


Asunto(s)
Acetiltransferasas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromátides/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Acetilación , Acetiltransferasas/química , Acetiltransferasas/genética , Sitios de Unión , Cromosomas Fúngicos/metabolismo , Mutación , Proteínas Nucleares/química , Proteínas Nucleares/genética , Unión Proteica , Estabilidad Proteica , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética
18.
Nat Commun ; 12(1): 1837, 2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33758202

RESUMEN

Oocytes are held in meiotic prophase for prolonged periods until hormonal signals trigger meiotic divisions. Key players of M-phase entry are the opposing Cdk1 kinase and PP2A-B55δ phosphatase. In Xenopus, the protein Arpp19, phosphorylated at serine 67 by Greatwall, plays an essential role in inhibiting PP2A-B55δ, promoting Cdk1 activation. Furthermore, Arpp19 has an earlier role in maintaining the prophase arrest through a second serine (S109) phosphorylated by PKA. Prophase release, induced by progesterone, relies on Arpp19 dephosphorylation at S109, owing to an unknown phosphatase. Here, we identified this phosphatase as PP2A-B55δ. In prophase, PKA and PP2A-B55δ are simultaneously active, suggesting the presence of other important targets for both enzymes. The drop in PKA activity induced by progesterone enables PP2A-B55δ to dephosphorylate S109, unlocking the prophase block. Hence, PP2A-B55δ acts critically on Arpp19 on two distinct sites, opposing PKA and Greatwall to orchestrate the prophase release and M-phase entry.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Meiosis , Oocitos/metabolismo , Fosfoproteínas/metabolismo , Proteína Fosfatasa 2/metabolismo , Proteínas de Xenopus/metabolismo , Animales , Proteína Quinasa CDC2/metabolismo , Cromatografía Liquida , Femenino , Meiosis/efectos de los fármacos , Meiosis/genética , Meiosis/fisiología , Proteínas Nucleares/metabolismo , Ácido Ocadaico/toxicidad , Fosfoproteínas Fosfatasas/metabolismo , Fosfoproteínas/genética , Fosforilación , Progesterona/farmacología , Proteína Fosfatasa 2/antagonistas & inhibidores , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/aislamiento & purificación , Proteínas Recombinantes , Espectrometría de Masas en Tándem , Proteínas de Xenopus/antagonistas & inhibidores , Proteínas de Xenopus/genética , Proteínas de Xenopus/aislamiento & purificación , Xenopus laevis
19.
Nat Commun ; 12(1): 1881, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767157

RESUMEN

To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies.


Asunto(s)
Carcinogénesis/patología , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/patología , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Cromosomas Humanos Par 17/genética , Variaciones en el Número de Copia de ADN/genética , Células HEK293 , Humanos , Ratones , Proteína Proto-Oncogénica N-Myc/genética , Neuroblastoma/genética , Proteínas Nucleares/genética , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/genética , Factores de Transcripción/genética , Transcripción Genética/genética , Activación Transcripcional/genética , Proteasas Ubiquitina-Específicas/genética , Ubiquitinación/fisiología
20.
Nat Cell Biol ; 23(3): 257-267, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33723425

RESUMEN

The complexity of intracellular signalling requires both a diversity of molecular players and the sequestration of activity to unique compartments within the cell. Recent findings on the role of liquid-liquid phase separation provide a distinct mechanism for the spatial segregation of proteins to regulate signalling pathway crosstalk. Here, we discover that DACT1 is induced by TGFß and forms protein condensates in the cytoplasm to repress Wnt signalling. These condensates do not localize to any known organelles but, rather, exist as phase-separated proteinaceous cytoplasmic bodies. The deletion of intrinsically disordered domains within the DACT1 protein eliminates its ability to both form protein condensates and suppress Wnt signalling. Isolation and mass spectrometry analysis of these particles revealed a complex of protein machinery that sequesters casein kinase 2-a Wnt pathway activator. We further demonstrate that DACT1 condensates are maintained in vivo and that DACT1 is critical to breast and prostate cancer bone metastasis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias Óseas/metabolismo , Neoplasias de la Mama/metabolismo , Movimiento Celular/efectos de los fármacos , Proteínas Nucleares/metabolismo , Neoplasias de la Próstata/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Proteína Wnt3A/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa de la Caseína II/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Invasividad Neoplásica , Proteínas Nucleares/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteína Wnt3A/genética
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