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Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term 'lncRNAs' encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates and domains, indicating an intimate link between lncRNA expression and the spatial control of gene expression during development. lncRNAs also have important roles in the cytoplasm and beyond, including in the regulation of translation, metabolism and signalling. lncRNAs often have a modular structure and are rich in repeats, which are increasingly being shown to be relevant to their function. In this Consensus Statement, we address the definition and nomenclature of lncRNAs and their conservation, expression, phenotypic visibility, structure and functions. We also discuss research challenges and provide recommendations to advance the understanding of the roles of lncRNAs in development, cell biology and disease.
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ARN Largo no Codificante , ARN Largo no Codificante/genética , Núcleo Celular/genética , Cromatina/genética , Secuencias Reguladoras de Ácidos Nucleicos , ARN Polimerasa II/genéticaRESUMEN
Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first example of a lncRNA-facilitated metabolon.
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Biomarcadores de Tumor/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/metabolismo , Glucólisis , Proteínas de la Membrana/metabolismo , Neoplasias/enzimología , Fosfoglicerato Quinasa/metabolismo , Fosfoglicerato Mutasa/metabolismo , Fosfopiruvato Hidratasa/metabolismo , ARN Largo no Codificante/metabolismo , Hormonas Tiroideas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Biomarcadores de Tumor/genética , Proteínas Portadoras/genética , Proliferación Celular , Proteínas de Unión al ADN/genética , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Proteínas de la Membrana/genética , Ratones Desnudos , Complejos Multienzimáticos , Neoplasias/genética , Neoplasias/patología , Fosfoglicerato Quinasa/genética , Fosfoglicerato Mutasa/genética , Fosfopiruvato Hidratasa/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Largo no Codificante/genética , Serina/deficiencia , Hormonas Tiroideas/genética , Carga Tumoral , Proteínas Supresoras de Tumor/genética , Proteínas de Unión a Hormona TiroideRESUMEN
Autophagy represents a fundamental mechanism for maintaining cell survival and tissue homeostasis in response to physiological and pathological stress. Autophagy initiation converges on the FIP200-ATG13-ULK1 complex wherein the serine/threonine kinase ULK1 plays a central role. Here, we reveal that the E3 ubiquitin ligase TRIM27 functions as a negative regulatory component of the FIP200-ATG13-ULK1 complex. TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels. However, during starvation-induced autophagy, TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1. This cooperative mechanism serves to restrain the amplitude and duration of autophagy. Further evidence from mouse models shows that basal autophagy levels are increased in Trim27 knockout mice and that Trim27 differentially regulates tumorigenesis and metastasis. Our study identifies a key role of STK38L-TRIM27-ULK1 signaling axis in negatively controlling autophagy with relevance established in human breast cancer.
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Autofagia , Proteínas Serina-Treonina Quinasas , Animales , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Carcinogénesis/genética , Proteínas de Unión al ADN , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Proteínas Nucleares , Proteínas Serina-Treonina Quinasas/genética , Serina , Factores de Transcripción , Ubiquitina-Proteína LigasasRESUMEN
Unveiling the principles governing embryonic stem cell (ESC) differentiation into specific lineages is critical for understanding embryonic development and for stem cell applications in regenerative medicine. Here, we establish an intersection between LIF-Stat3 signaling that is essential for maintaining murine (m) ESCs pluripotency, and the glycolytic enzyme, the platelet isoform of phosphofructokinase (Pfkp). In the pluripotent state, Stat3 transcriptionally suppresses Pfkp in mESCs while manipulating the cells to lift this repression results in differentiation towards the ectodermal lineage. Pfkp exhibits substrate specificity changes to act as a protein kinase, catalyzing serine phosphorylation of the developmental regulator Lin41. Such phosphorylation stabilizes Lin41 by impeding its autoubiquitination and proteasomal degradation, permitting Lin41-mediated binding and destabilization of mRNAs encoding ectodermal specification markers to favor the expression of endodermal specification genes. This provides new insights into the wiring of pluripotency-differentiation circuitry where Pfkp plays a role in germ layer specification during mESC differentiation.
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Fosfofructoquinasas , Proteínas Quinasas , Embarazo , Femenino , Ratones , Animales , Proteínas Quinasas/metabolismo , Fosfofructoquinasas/metabolismo , Células Madre Embrionarias/metabolismo , Diferenciación Celular/genética , Transducción de Señal , Células Madre Embrionarias de Ratones/metabolismoRESUMEN
Astrocytic excitatory amino acid transporter 2 (EAAT2) plays a major role in removing the excitatory neurotransmitter L-glutamate (L-Glu) from synaptic clefts in the forebrain to prevent excitotoxicity. Polyunsaturated fatty acids such as docosahexaenoic acid (DHA, 22:6 n-3) enhance synaptic transmission, and their target molecules include EAATs. Here, we aimed to investigate the effect of DHA on EAAT2 and identify the key amino acid for DHA/EAAT2 interaction by electrophysiological recording of L-Glu-induced current in Xenopus oocytes transfected with EAATs, their chimeras, and single mutants. DHA transiently increased the amplitude of EAAT2 but tended to decrease that of excitatory amino acid transporter subtype 1 (EAAT1), another astrocytic EAAT. Single mutation of leucine (Leu) 434 to alanine (Ala) completely suppressed the augmentation by DHA, while mutation of EAAT1 Ala 435 (corresponding to EAAT2 Leu434) to Leu changed the effect from suppression to augmentation. Other polyunsaturated fatty acids (docosapentaenoic acid, eicosapentaenoic acid, arachidonic acid, and α-linolenic acid) similarly augmented the EAAT2 current and suppressed the EAAT1 current. Finally, our docking analysis suggested the most stable docking site is the lipid crevice of EAAT2, in close proximity to the L-Glu and sodium binding sites, suggesting that the DHA/Leu434 interaction might affect the elevator-like slide and/or the shapes of the other binding sites. Collectively, our results highlight a key molecular detail in the DHA-induced regulation of synaptic transmission involving EAATs.
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Ácidos Docosahexaenoicos , Transportador 2 de Aminoácidos Excitadores , Transmisión Sináptica , Xenopus laevis , Ácidos Docosahexaenoicos/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Transportador 2 de Aminoácidos Excitadores/metabolismo , Ácido Glutámico/metabolismo , Leucina , Mutación , Xenopus laevis/metabolismoRESUMEN
TRIM family proteins are widely found in multicellular organisms and are involved in a wide range of life activities, and also act as crucial regulators in the antiviral natural immune response. This study aimed to reveal the molecular mechanism of rainbow trout TRIM protein in the anti-IHNV process. The results demonstrated that 99.1 % homology between the rainbow trout and the chinook salmon (Oncorhynchus tshawytscha) TRIM32. When rainbow trout were infected with IHNV, the TRIM32 was highly expressed in the gill, spleen, kidney and blood. Meanwhile, rainbow trout TRIM32 has E3 ubiquitin ligase activity and undergoes K29-linked polyubiquitination modifications dependent on the RING structural domain was determined by immunoprecipitation. TRIM32 could interact with the NV protein of IHNV and degrade NV protein through the ubiquitin-proteasome pathway, and was also able to activate NF-κB transcription, thereby inhibiting the replication of IHNV. Moreover, the results of the animal studies showed that the survival rate of rainbow trout overexpressing TRIM32 was 70.2 % which was significantly higher than that of the control group, and stimulating the body to produce high levels of IgM when the host was infected with the virus. In addition, TRIM32 can activate the NF-κB signalling pathway and participate in the antiviral natural immune response. The results of this study will help us to understand the molecular mechanism of TRIM protein resistance in rainbow trout, and provide new ideas for disease resistance breeding, vaccine development and immune formulation development in rainbow trout.
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Duck circovirus (DuCV) is one of the most prevalent infectious viruses in the duck industry in China. Although the clinical signs vary, it often causes immunosuppression in the host and leads to secondary infection with other pathogens. Novel goose parvovirus (NGPV) mainly infects ducks and causes short beak and dwarfism syndrome in ducks. However, the incidence of infection in ducks has increased in recent years, and the phenomenon of mixed infection with DuCV is common, resulting in more severe clinical morbidity. However, there are no systematic studies evaluating the presence of mixed infections. In order to investigate the synergistic pathogenicity of DuCV and NGPV co-infection in SPF ducks, a comparative experiment using DuCV and NGPV co-infection and mono-infection bird models was established. The results showed that the clinical signs of short beak, dwarfism and immunosuppression were more obvious in DuCV and NGPV co-infected ducks; the tissue damage of target organs was more serious, and the viral titre in organs and cloacal swabs were more significant compared with those of SPF ducks infected with only one virus. The results indicated that co-infection with DuCV and NGPV could promote viral replication and cause more severe tissue damage and immunosuppression than single virus infection. The present study reveals that the co-infection of NGPV and DuCV has a synergistic pathogenic effect from the aspect of pathogenicity, and the conclusions drawn not only clarify the direction of the subsequent research on the mechanism of co-infection of NGPV and DuCV, but also provide a scientific basis for the research on the co-infection of immunosuppressive pathogens and other pathogens.
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Objective: Network pharmacology is an emerging discipline that applies computational methods to understand drug actions and interactions with multiple molecular targets. Xiao'ai Jiedu is a valued traditional Chinese medicine preparation for which the mechanism of action is not yet established. This study aims to explore the mechanism of Xiao'ai Jiedu in treating lung cancer through network pharmacology. Methods: First, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) data platform was used to analyze the target treatment results of different medicinal materials in Mr. Zhou's cancer prescriptions. Then, functional enrichment analysis was performed to conduct a secondary analysis of the dissemination of cancer biological and pharmacological information in the human body. The Cancer Genome Atlas (TCGA) was used to obtain several cancer-aggressive target groups, and their transcription RNA was extracted for collection. The CIBERSORT evaluation method was used to conduct a Spearman correlation analysis on the data processing results. Then the matching degree between the experimental cells and the principle of drug treatment was analyzed to improve the statistical analysis. Results: Pharmacology research results showed that the network can accurately eliminate cancer detoxification targeted target correlation set, and through the data interpretation found that four different gene transcription have significant influence on lung cancer. The findings also confirmed that the degree of immune cell infiltration has a key role in lung cancer The study summarizes the active ingredients and their targets and mechanisms of action of the elimination of Xiao'ai Jiedu formula for the treatment of lung cancer. Conclusion: Network pharmacology can carry on the processing of the data, find the key to conform to the goal of research data, and the corresponding results are obtained, and the development of network pharmacology is not limited to, the study of lung cancer.
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According to the theory of five movements and six climates, the innate constitution plays a crucial role in determining the underlyingpa thological mechanisms of diseases later in life. Previous studies have demonstrated a close association between the constitution, as defined by the theory of five movements and six climates, and the development of various types of tumors. Furt hermore,the tumorsubtype determined by the constitution has prognostic implications. This highlights the potential of utilizing the fivemovements and six climates theory to guide the implementation of precision medicine strategies in thefield of oncology. However, no resear ch has yet been conducted to investigate the use of this theory in guiding the development of tumor molecular classification and precisi onmedicine strategies. The objective of this research is to uncover the biological characteristics of each constitution within a pancanc ercohort and identify potential anti-tumor drugs that are applicable to patients with different constitutional types. By doing so, we aimto c ontribute to the establishment of a precision medicine strategy for tumors derived from the original concepts of traditional Chi nesemedicine(TCM). In this study, we obtainedpan-cancer Bulk RNA-Seq data from UCSC Xena, GWAS cohort data from the UKBiobank, and cis-eQTLs data from eQ TLGen and GTEx V8. We employed machine learning methods to screen for hub genes associated with each constitution. Subsequently, we utilized informatics tools to explore the biological characteristics of each constitut iondefined by the theory of five movements and six bioclimates. Further, potential anti-tumor drugs suitable for patients with differen tconstitutional types were identified through mendelian randomization, molecular docking, and drug-like prediction techniques. Withinthe pan-cancer cohort, significant differences were observed among different constitutions in terms of progression-free interval, biological f unctions, immune cell abundance, tumor drug sensitivity, and immunotherapy response. These findings suggest that the five movements and six climates theory can guide tumor molecular classification and the development of precision medicine strategies. Moreover,the biological characteristics inherent to each constitution partially shed light on the scientific implications of Chinese medicinetheories, offering a fresh perspective towards clinical cancer treatment. Through molecular docking and drug-like prediction, several po tential anti-tumor drugs such as 17-beta-estradiol, serotonin, trans-resveratrol, and linoleic acid were identified. Overall, the util izationof multi-omics approaches pro vides a powerful tool to unravel the scientific foundations of TCM theories. The elucidation of themu lti-omics features associated witheach constitution in tumors serves as the basis for applying the five movements and six climates theoryto tumor molecular classification and the development of precision medicine strategies.
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Neoplasias , Humanos , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Medicina de Precisión , RNA-Seq , Medicina Tradicional China , Constitución Corporal/genéticaRESUMEN
BACKGROUND: Although the executive pathways of senescence are known, the underlying control mechanisms are diverse and not fully understood, particularly how cancer cells avoid triggering senescence despite experiencing exacerbated stress conditions within the tumor microenvironment. METHODS: Mass spectrometry (MS)-based proteomic screening was used to identify differentially regulated genes in serum-starved hepatocellular carcinoma cells and RNAi employed to determine knockdown phenotypes of prioritized genes. Thereafter, gene function was investigated using cell proliferation assays (colony-formation, CCK-8, Edu incorporation and cell cycle) together with cellular senescence assays (SA-ß-gal, SAHF and SASP). Gene overexpression and knockdown techniques were applied to examine mRNA and protein regulation in combination with luciferase reporter and proteasome degradation assays, respectively. Flow cytometry was applied to detect changes in cellular reactive oxygen species (ROS) and in vivo gene function examined using a xenograft model. RESULTS: Among the genes induced by serum deprivation, NIPSNAP1 was selected for investigation. Subsequent experiments revealed that NIPSNAP1 promotes cancer cell proliferation and inhibits P27-dependent induction of senescence via dual mechanisms. Firstly, NIPSNAP1 maintains the levels of c-Myc by sequestering the E3 ubiquitin ligase FBXL14 to prevent the proteasome-mediated turnover of c-Myc. Intriguingly, NIPSNAP1 levels are restrained by transcriptional repression mediated by c-Myc-Miz1, with repression lifted in response to serum withdrawal, thus identifying feedback regulation between NIPSNAP1 and c-Myc. Secondly, NIPSNAP1 was shown to modulate ROS levels by promoting interactions between the deacetylase SIRT3 and superoxide dismutase 2 (SOD2). Consequent activation of SOD2 serves to maintain cellular ROS levels below the critical levels required to induce cell cycle arrest and senescence. Importantly, the actions of NIPSNAP1 in promoting cancer cell proliferation and preventing senescence were recapitulated in vivo using xenograft models. CONCLUSIONS: Together, these findings reveal NIPSNAP1 as an important mediator of c-Myc function and a negative regulator of cellular senescence. These findings also provide a theoretical basis for cancer therapy where targeting NIPSNAP1 invokes cellular senescence.
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Neoplasias , Complejo de la Endopetidasa Proteasomal , Humanos , Especies Reactivas de Oxígeno/metabolismo , Proteómica , Neoplasias/genética , Línea Celular , Senescencia Celular/genética , Microambiente Tumoral , Péptidos y Proteínas de Señalización IntercelularRESUMEN
We disclose a transporting/collecting optical sling generated by a liquid crystal geometric phase optical element with spatial variant topological charge, which shows the intriguing repelling/indrawing effect on the micro-particle along the spiral orbit. Two proof-of-concept prototypes, i.e., an optical conveyor and a particle collector, are demonstrated. Based on the distinct dynamic characteristics of the micro-particles in different sizes, we conceptually propose a design for particle sorting. Thus, our proposed method to generate a spiral optical sling with spatial variant orbital angular momentum for on-demand collecting, transporting and sorting micro-particles is substantiated, which can find extensive applications in bio-medicine, micro-biology, etc.
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Exploiting the pluripotent properties of embryonic stem cells (ESCs) holds great promise for regenerative medicine. Nevertheless, directing ESC differentiation into specialized cell lineages requires intricate control governed by both intrinsic and extrinsic factors along with the actions of specific signaling networks. Here, we reveal the involvement of the p21-activated kinase 4 (Pak4), a serine/threonine kinase, in sustaining murine ESC (mESC) pluripotency. Pak4 is highly expressed in R1 ESC cells compared with embryonic fibroblast cells and its expression is progressively decreased during differentiation. Manipulations using knockdown and overexpression demonstrated a positive relationship between Pak4 expression and the clonogenic potential of mESCs. Moreover, ectopic Pak4 expression increases reprogramming efficiency of Oct4-Klf4-Sox2-Myc-induced pluripotent stem cells (iPSCs) whereas Pak4-knockdown iPSCs were largely incapable of generating teratomas containing mesodermal, ectodermal and endodermal tissues, indicative of a failure in differentiation. We further establish that Pak4 expression in mESCs is transcriptionally driven by the core pluripotency factor Nanog which recognizes specific binding motifs in the Pak4 proximal promoter region. In turn, the increased levels of Pak4 in mESCs fundamentally act as an upstream activator of the Akt pathway. Pak4 directly binds to and phosphorylates Akt at Ser473 with the resulting Akt activation shown to attenuate downstream GSK3ß signaling. Thus, our findings indicate that the Nanog-Pak4-Akt signaling axis is essential for maintaining mESC self-renewal potential with further importance shown during somatic cell reprogramming where Pak4 appears indispensable for multi-lineage specification.
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Proteínas Proto-Oncogénicas c-akt , Quinasas p21 Activadas , Animales , Ratones , Diferenciación Celular , Reprogramación Celular , Células Madre Embrionarias/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina/metabolismoRESUMEN
PURPOSE: Segmentation of liver vessels from CT images is indispensable prior to surgical planning and aroused a broad range of interest in the medical image analysis community. Due to the complex structure and low-contrast background, automatic liver vessel segmentation remains particularly challenging. Most of the related researches adopt FCN, U-net, and V-net variants as a backbone. However, these methods mainly focus on capturing multi-scale local features which may produce misclassified voxels due to the convolutional operator's limited locality reception field. METHODS: We propose a robust end-to-end vessel segmentation network called Inductive BIased Multi-Head Attention Vessel Net(IBIMHAV-Net) by expanding swin transformer to 3D and employing an effective combination of convolution and self-attention. In practice, we introduce voxel-wise embedding rather than patch-wise embedding to locate precise liver vessel voxels and adopt multi-scale convolutional operators to gain local spatial information. On the other hand, we propose the inductive biased multi-head self-attention which learns inductively biased relative positional embedding from initialized absolute position embedding. Based on this, we can gain more reliable queries and key matrices. RESULTS: We conducted experiments on the 3DIRCADb dataset. The average dice and sensitivity of the four tested cases were 74.8[Formula: see text] and 77.5[Formula: see text], which exceed the results of existing deep learning methods and improved graph cuts method. The Branches Detected(BD)/Tree-length Detected(TD) indexes also proved the global/local feature capture ability better than other methods. CONCLUSION: The proposed model IBIMHAV-Net provides an automatic, accurate 3D liver vessel segmentation with an interleaved architecture that better utilizes both global and local spatial features in CT volumes. It can be further extended for other clinical data.
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Cabeza , Hígado , Humanos , Hígado/diagnóstico por imagen , Atención , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
The direct C-H multifunctionalization of quinoxalin-2(1H)-ones via multicomponent reactions has attracted considerable interest due to their diverse biological activities and chemical profile. This review will focus on recent achievements. It mainly covers reaction methods for the simultaneous introduction of C-C bonds and C-RF/C/O/N/Cl/S/D bonds into quinoxalin-2(1H)-ones and their reaction mechanisms. Meanwhile, future developments of multi-component reactions of quinoxalin-2(1H)-ones are envisaged, such as the simultaneous construction of C-C and C-B/SI/P/F/I/SE bonds through multi-component reactions; the construction of fused ring and macrocyclic compounds; asymmetric synthesis; green chemistry; bionic structures and other fields. The aim is to enrich the methods for the reaction of quinoxalin-2(1H)-ones at the C3 position, which have rich applications in materials chemistry and pharmaceutical pharmacology.
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The TP53 gene is arguably the most important tumor suppressor gene known, contributing multifaceted roles to the process of tumor development. Its protein product p53, is a crucial sequence-specific transcription factor which regulates the expression of a large network of protein-coding genes, as well as thousands of noncoding RNAs (ncRNAs), notably microRNAs and long ncRNAs (lncRNAs). Through a variety of direct and indirect mechanisms, ncRNAs in turn modulate p53 levels and activity. Here the numbers of studies are steadily building which link the contributions of dysregulated ncRNAs to tumorigenesis via their participation throughout the p53 regulatory network. In this review, we will examine how the principal forms of ncRNAs, namely microRNAs, lncRNAs and circular RNAs (circRNAs) function as either effectors or regulators amongst the diversity of p53's cellular responses. We first discuss the more recently discovered connections between miRNAs and p53 signaling before focusing on the remarkable diversity of crosstalk evident between lncRNAs and p53, and subsequently, developing reports linking circRNAs to p53. Highlighted throughout the review are the mechanistic impacts of dysregulated ncRNAs on p53 functions as well as the possible prognostic implications of these interactions. We also describe the emerging connections between ncRNAs and the often-perplexing functions of mutant p53. Finally, in the context of p53 therapeutic approaches, we describe some of the challenges in ncRNA research and their potential for translation.
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Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Mutación , Neoplasias/patología , ARN Largo no Codificante/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Biomarcadores de Tumor/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The long noncoding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions toward senescence or apoptosis, but the underlying molecular signals are unknown. Here, we show that GUARDIN is an essential component of a transcriptional repressor complex involving LRP130 and PGC1α. GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and their occupancy at the FOXO4 promotor. Destabilizing this complex by silencing of GUARDIN, LRP130, or PGC1α leads to increased expression of FOXO4 and upregulation of its target gene p21, thereby driving cells into senescence. We also found that GUARDIN expression was induced by rapamycin, an agent that suppresses cell senescence. FOS-like antigen 2 (FOSL2) acts as a transcriptional repressor of GUARDIN, and lower FOSL2 levels in response to rapamycin correlate with increased levels of GUARDIN. Together, these results demonstrate that GUARDIN inhibits p21-dependent senescence through a LRP130-PGC1α-FOXO4 signaling axis, and moreover, GUARDIN contributes to the anti-aging activities of rapamycin.
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Senescencia Celular , ARN Largo no Codificante , Transducción de Señal , Apoptosis , Proteínas de Ciclo Celular , Senescencia Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Factores de Transcripción Forkhead , Humanos , Proteínas de Neoplasias , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gammaRESUMEN
Hypoxia has long been linked to the Warburg effect, yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs are involved in the contribution of hypoxia to the Warburg effect. Here we show that lincRNA-p21 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis. Hypoxia/HIF-1α-induced lincRNA-p21 is able to bind HIF-1α and VHL and thus disrupts the VHL-HIF-1α interaction. This disassociation attenuates VHL-mediated HIF-1α ubiquitination and causes HIF-1α accumulation. These data indicate the existence of a positive feedback loop between HIF-1α and lincRNA-p21 that promotes glycolysis under hypoxia. The ability of lincRNA-p21 to promote tumor growth is validated in mouse xenograft models. Together, these findings suggest that lincRNA-p21 is an important player in the regulation of the Warburg effect and also implicate lincRNA-p21 as a valuable therapeutic target for cancer.
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Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , ARN Largo no Codificante/metabolismo , ARN Neoplásico/metabolismo , Animales , Hipoxia de la Célula/genética , Células HeLa , Xenoinjertos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , Trasplante de Neoplasias , Neoplasias/genética , Neoplasias/patología , ARN Largo no Codificante/genética , ARN Neoplásico/genética , Ubiquitinación/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
Long non-coding RNAs (lncRNAs) have emerged as important biological tuners. Here, we reveal the role of an uncharacterized lncRNA we call SENEBLOC that is expressed by both normal and transformed cells under homeostatic conditions. SENEBLOC was shown to block the induction of cellular senescence through dual mechanisms that converge to repress the expression of p21. SENEBLOC facilitates the association of p53 with MDM2 by acting as a scaffold to promote p53 turnover and decrease p21 transactivation. Alternatively, SENEBLOC was shown to affect epigenetic silencing of the p21 gene promoter through regulation of HDAC5. Thus SENEBLOC drives both p53-dependent and p53-independent mechanisms that contribute to p21 repression. Moreover, SENEBLOC was shown to be involved in both oncogenic and replicative senescence, and from the perspective of senolytic agents we show that the antagonistic actions of rapamycin on senescence are dependent on SENEBLOC expression.
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Envejecimiento/genética , Neoplasias/genética , ARN Largo no Codificante/genética , Proteína p53 Supresora de Tumor/genética , Animales , Carcinogénesis/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica/genética , Células HCT116 , Xenoinjertos , Histona Desacetilasas/genética , Humanos , Ratones , Unión Proteica/genética , Transducción de Señal/genéticaRESUMEN
The use of photosensitive proteins has become a competitive solar energy solution, owing to its pollution-free nature, high conversion efficiency, and good biocompatibility. Bacteriorhodopsin (bR) is an important light-sensitive protein that is widely used in the fabrication of photoelectronic devices. However, research on the optimization and comparison of the immobilization techniques is lacking. In this study, in order to obtain bR films with a high energy conversion efficiency, three immobilization techniques, namely dropcasting, electrophoretic sedimentation, and Langmuir-Blodgett deposition, were used to fabricate films, and their topographical and photoelectrical characteristics were compared. All three immobilization techniques can transfer bR molecules to substrates, forming functional photosensitive bR films. The absorption of the bR films at 568 nm reached the highest value of 0.3 under the EPS technique. The peak photocurrent for the EPS technique reached 5.03 nA. In addition, the EPS technique has the highest efficiency factor of 13.46, indicating that it can generate the highest value of photocurrent under the same light conditions, owing to the improved orientation, and no significant decrease in the peak photocurrent was observed after three weeks, which indicates the stability of the photoelectric response. These results indicate that the EPS technique has a great potential for the photoelectrical device fabrication and solar-energy conversion.
Asunto(s)
Bacteriorodopsinas , Bacteriorodopsinas/químicaRESUMEN
Applying pesticides can result in emissions of volatile organic compounds (VOCs), but little is known about VOC emission characteristics and the quantities in particular regions. We investigated the use of pesticides in China based on a large-scale survey of 330 counties in 31 provinces and evaluated the national pesticide VOC emission potentials based on thermogravimetric analysis of 1930 commercial pesticides. The results showed that herbicides were the most extensively used pesticide category in China, accounting for 43.47%; emulsifiable concentrate (EC), suspension concentrate, and wettable powder were the dominant pesticide formulations, with proportions of 26.75%, 17.68%, and 17.31%, respectively. The VOC emission potential coefficient (EP) of the liquid formulations was higher than the solid formulations, and the maximum mean EP was 45.59% for EC and the minimum was 0.76% for WP. Among 437 high-VOC pesticide products used in China, EC accounted for 83.52%, and 16.93% of those contained abamectin. The total VOC emissions derived from commercial pesticides in China were 280 kt (kilotons) in 2018, and 65.35% of the contribution was derived from EC. Shandong, Hunan, and Henan were the three provinces with the highest pesticide VOC emissions (>21 kt/y). The emission rate of VOCs from pesticides was 24.80 t/d in China, which was higher than in San Joaquin Valley, California. These findings suggest that some comprehensive measures (e.g., perfecting pesticide management policy, strict supervision for pesticide production and use, and strengthening pesticide reduction publicity) should be taken to reduce VOC emissions from pesticide applications.