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1.
Water Sci Technol ; 83(6): 1347-1356, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33767041

RESUMEN

The rapid overcompensatory growth that appears when cyanobacteria are supplied with adequate resources after a period of resource deprivation might contribute to the occurrence of cyanobacterial blooms. We investigated the changing characteristics of overcompensatory growth and serine/threonine kinase (STK) genes expression of cyanobacterium Microcystis aeruginosa in response to light limitation. The results showed M. aeruginosa exhibited overcompensatory growth for 2 days after light recovery, during which the increase in growth was inversely related to light intensity. Expression of STK genes, such as spkD, was upregulated significantly at 0.5-4 h after light recovery (P < 0.05). To investigate the function of STK genes in the overcompensatory growth, M. aeruginosa spkD was heterologously expressed in Synechocystis. Transgenic Synechocystis exhibited greater and longer overcompensatory growth than wild-type Synechocystis after light recovery. Relative expression levels of STK genes in transgenic Synechocystis were significantly higher than those in wild-type Synechocystis at 24 h of light recovery (P < 0.05). Heterologous expression of Microcystis spkD might stimulate overcompensatory growth of Synechocystis by affecting its STK gene expression.


Asunto(s)
Proteínas Bacterianas , Synechocystis , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Serina , Synechocystis/genética , Synechocystis/metabolismo
2.
Nat Commun ; 12(1): 1736, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741957

RESUMEN

Metastasis is the leading cause of cancer-related death. Despite the recent advancements in cancer treatment, there is currently no approved therapy for metastasis. The present study reveals a potent and selective activity of PRAK in the regulation of tumor metastasis. While showing no apparent effect on the growth of primary breast cancers or subcutaneously inoculated tumor lines, Prak deficiency abrogates lung metastases in PyMT mice or mice receiving intravenous injection of tumor cells. Consistently, PRAK expression is closely associated with metastatic risk in human cancers. Further analysis indicates that loss of function of PRAK leads to a pronounced inhibition of HIF-1α protein synthesis, possibly due to reduced mTORC1 activities. Notably, pharmacological inactivation of PRAK with a clinically relevant inhibitor recapitulates the anti-metastatic effect of Prak depletion, highlighting the therapeutic potential of targeting PRAK in the control of metastasis.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metástasis de la Neoplasia , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Neoplasias de la Mama , Línea Celular Tumoral , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Neoplasias/terapia , Proteínas Serina-Treonina Quinasas/genética
3.
Nat Commun ; 12(1): 1731, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741962

RESUMEN

Mutations in KCNC3, which encodes the Kv3.3 potassium channel, cause degeneration of the cerebellum, but exactly how the activity of an ion channel is linked to the survival of cerebellar neurons is not understood. Here, we report that Kv3.3 channels bind and stimulate Tank Binding Kinase 1 (TBK1), an enzyme that controls trafficking of membrane proteins into multivesicular bodies, and that this stimulation is greatly increased by a disease-causing Kv3.3 mutation. TBK1 activity is required for the binding of Kv3.3 to its auxiliary subunit Hax-1, which prevents channel inactivation with depolarization. Hax-1 is also an anti-apoptotic protein required for survival of cerebellar neurons. Overactivation of TBK1 by the mutant channel leads to the loss of Hax-1 by its accumulation in multivesicular bodies and lysosomes, and also stimulates exosome release from neurons. This process is coupled to activation of caspases and increased cell death. Our studies indicate that Kv3.3 channels are directly coupled to TBK1-dependent biochemical pathways that determine the trafficking of cellular constituents and neuronal survival.


Asunto(s)
Supervivencia Celular/fisiología , Cerebelo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transporte de Proteínas/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Canales de Potasio Shaw/metabolismo , Animales , Exosomas/metabolismo , Femenino , Interneuronas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Mutación , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Canales de Potasio Shaw/genética , Transducción de Señal
4.
Plant Physiol Biochem ; 160: 377-385, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33550178

RESUMEN

The nonreducing disaccharide trehalose is widespread in nature. It plays a very important role in plant growth and development. In plants, trehalose is present in trace amounts. High concentration of trehalose disrupts energy balance and inhibits normal growth and development. Studies have shown that high levels of trehalose and trehalose-6-phosphate (T6P), the metabolic precursor of trehalose, inhibit sucrose non-fermenting-1-related protein kinase1 (SnRK1) activity, which affect plant growth and development. However, the role of SnRK1, the energy balance center, in the regulation of trehalose metabolism in plants is unknown. In this study, exogenous trehalose at higher concentrations inhibited the expression of SnRK1 genes, especially PpSnRK1α in peach (Prunus persica) seedlings. This change in gene expression was dependent on trehalose concentration. Furthermore, overexpression of peach PpSnRK1α in Arabidopsis thaliana significantly promoted trehalase activity, reduced T6P content, and suppressed the trehalose synthesis related genes (TPSs, TPPB) expression, promoted the trehalose metabolism of gene expression (TRE1), in addition the transgenic plants alleviated photosynthetic product distribution imbalance (aboveground and underground parts), and enhanced root growth. Yeast two-hybrid and bimolecular fluorescence assays revealed the interaction between PpSnRK1α and peach basic domain leucine zipper transcription factor 11 (PpbZIP11), a key transcription factor of trehalose metabolism, in the nucleus. To summarize, PpSnRK1α overexpression improved bZIP11 transcriptional activity and regulated trehalose metabolism to protect the plants against trehalose-induced damage. This study preliminarily explained the mechanism of SnRK1 regulating trehalose metabolism balance in plants, which laid a foundation for further understanding of energy metabolism and function of SnRK1 in plants.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Prunus persica/genética , Trehalosa/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Regulación de la Expresión Génica de las Plantas , Plantas Modificadas Genéticamente/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Fosfatos de Azúcar
5.
Nat Commun ; 12(1): 836, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547321

RESUMEN

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3ß inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.


Asunto(s)
Colitis/genética , Glucógeno Sintasa Quinasa 3 beta/genética , Homeostasis/genética , Interleucina-33/genética , Proteínas de la Membrana/genética , Proteínas Serina-Treonina Quinasas/genética , Animales , Recuento de Células , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Niño , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Femenino , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Células Caliciformes/patología , Células HT29 , Homeostasis/efectos de los fármacos , Humanos , Interleucina-33/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Dodecil Sulfato de Sodio/administración & dosificación
6.
Gene ; 777: 145466, 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33524518

RESUMEN

The dopamine - related genes, like dopamine D2 receptor (DRD2) gene and ankyrin repeat and kinase domain containing 1 (ANKK1) gene are implicated in neurological functions. Some polymorphisms of the DRD2/ANKK1 locus (TaqIA, TaqIB, TaqID) have been used to study genetic diversity and the evolution of human populations. The present investigation aims to assess the genetic diversity in seven North African populations in order to explore their genetic structure and to compare them to others worldwide populations studied for the same locus. Nine single nucleotide polymorphisms (SNPs) from the DRD2/ANKK1 locus (rs1800497 TaqIA, rs2242592, rs1124492, rs6277, rs6275, rs1079727, rs2002453, rs2234690 and rs1079597 TaqIB) were typed in 366 individuals from seven North African populations: six from Tunisia (Sousse, Smar, Kesra, Kairouan, Mehdia and Kerkennah) and one from Libya. The allelic frequencies of rs2002453 and rs2234690 were higher in the Smar population than in the other North African populations. More, the Smar population showed the lowest average heterozygosity (0.313). The principal component analysis (PCA) showed that the Smar population was clearly separated from others. Furthermore, linkage disequilibrium analysis shown a high linkage disequilibrium in the North African population and essentially in Smar population. Comparison with other world populations has shown that the heterozygosity of North African population was very close to that of the African and European populations. The PCA and the haplotypic analysis suggested the presence of an important Eurasian genetic component for the North African population. These results suggested that the Smar population was isolated from the others North Africans ones by its peculiar genetic structure because of isolation, endogamy and genetic drift. On the other hand, the North African population is characterized by a multi ancestral gene pool from Eurasia and sub-Saharan Africa due to human migration since prehistoric times.


Asunto(s)
Proteínas Serina-Treonina Quinasas/genética , Receptores de Dopamina D2/genética , Adulto , África del Norte/etnología , Grupo de Ascendencia Continental Africana , Alelos , Grupos Étnicos/genética , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Genómica , Genotipo , Técnicas de Genotipaje , Haplotipos/genética , Heterocigoto , Migración Humana , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética
7.
Crit Rev Oncol Hematol ; 159: 103246, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33545354

RESUMEN

The HIPPO pathway (HP) is a highly conserved kinase cascade that affects organ size by regulating proliferation, cell survival and differentiation. Discovered in Drosophila melanogaster to early 2000, it immediately opened wide frontiers in the field of research. Over the last years the field of knowledge on HP is quickly expanding and it is thought will offer many answers on complex pathologies. Here, we summarized the results of several studies that have investigated HP signaling both in oncology than in cardiology field, with an overview on future perspectives in cardiology research.


Asunto(s)
Cardiología , Drosophila melanogaster , Animales , Proliferación Celular , Drosophila melanogaster/metabolismo , Humanos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal
8.
Mol Cell ; 81(3): 426-441.e8, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33545059

RESUMEN

Eukaryotic genomes replicate via spatially and temporally regulated origin firing. Cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) promote origin firing, whereas the S phase checkpoint limits firing to prevent nucleotide and RPA exhaustion. We used chemical genetics to interrogate human DDK with maximum precision, dissect its relationship with the S phase checkpoint, and identify DDK substrates. We show that DDK inhibition (DDKi) leads to graded suppression of origin firing and fork arrest. S phase checkpoint inhibition rescued origin firing in DDKi cells and DDK-depleted Xenopus egg extracts. DDKi also impairs RPA loading, nascent-strand protection, and fork restart. Via quantitative phosphoproteomics, we identify the BRCA1-associated (BRCA1-A) complex subunit MERIT40 and the cohesin accessory subunit PDS5B as DDK effectors in fork protection and restart. Phosphorylation neutralizes autoinhibition mediated by intrinsically disordered regions in both substrates. Our results reveal mechanisms through which DDK controls the duplication of large vertebrate genomes.


Asunto(s)
Replicación del ADN , Origen de Réplica , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Replicación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Puntos de Control de la Fase S del Ciclo Celular , Especificidad por Sustrato , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Xenopus laevis
9.
BMC Pulm Med ; 21(1): 58, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33588817

RESUMEN

BACKGROUND: Hyperoxia downregulates the tight junction (TJ) proteins of the alveolar epithelium and leads to barrier dysfunction. Previous study has showed that STE20/SPS1-related proline/alanine-rich kinase (SPAK) interferes with the intestinal barrier function in mice. The aim of the present study is to explore the association between SPAK and barrier function in the alveolar epithelium after hyperoxic exposure. METHODS: Hyperoxic acute lung injury (HALI) was induced by exposing mice to > 99% oxygen for 64 h. The mice were randomly allotted into four groups comprising two control groups and two hyperoxic groups with and without SPAK knockout. Mouse alveolar MLE-12 cells were cultured in control and hyperoxic conditions with or without SPAK knockdown. Transepithelial electric resistance and transwell monolayer permeability were measured for each group. In-cell western assay was used to screen the possible mechanism of p-SPAK being induced by hyperoxia. RESULTS: Compared with the control group, SPAK knockout mice had a lower protein level in the bronchoalveolar lavage fluid in HALI, which was correlated with a lower extent of TJ disruption according to transmission electron microscopy. Hyperoxia down-regulated claudin-18 in the alveolar epithelium, which was alleviated in SPAK knockout mice. In MLE-12 cells, hyperoxia up-regulated phosphorylated-SPAK by reactive oxygen species (ROS), which was inhibited by indomethacin. Compared with the control group, SPAK knockdown MLE-12 cells had higher transepithelial electrical resistance and lower transwell monolayer permeability after hyperoxic exposure. The expression of claudin-18 was suppressed by hyperoxia, and down-regulation of SPAK restored the expression of claudin-18. The process of SPAK suppressing the expression of claudin-18 and impairing the barrier function was mediated by p38 mitogen-activated protein kinase (MAPK). CONCLUSIONS: Hyperoxia up-regulates the SPAK-p38 MAPK signal pathway by ROS, which disrupts the TJ of the alveolar epithelium by suppressing the expression of claudin-18. The down-regulation of SPAK attenuates this process and protects the alveolar epithelium against the barrier dysfunction induced by hyperoxia.


Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Células Epiteliales Alveolares/metabolismo , Claudinas/genética , Hiperoxia/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Alveolos Pulmonares/metabolismo , Uniones Estrechas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Lesión Pulmonar Aguda/patología , Células Epiteliales Alveolares/ultraestructura , Animales , Líquido del Lavado Bronquioalveolar/química , Claudinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Hiperoxia/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Permeabilidad , Proteínas Serina-Treonina Quinasas/metabolismo , Alveolos Pulmonares/ultraestructura , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Uniones Estrechas/ultraestructura
10.
Plant Mol Biol ; 105(6): 685-696, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33543389

RESUMEN

KEY MESSAGE: This work demonstrates that PpCIPK1, a putative protein kinase, participates in regulating plant salt tolerance in moss Physcomitrella patens. Calcineurin B-Like protein (CBL)-interacting protein kinases (CIPKs) have been reported to be involved in multiple signaling networks and function in plant growth and stress responses, however, their biological functions in non-seed plants have not been well characterized. In this study, we report that PpCIPK1, a putative protein kinase, participates in regulating plant salt tolerance in moss Physcomitrella patens (P. patens). Phylogenetic analysis revealed that PpCIPK1 shared high similarity with its homologs in higher plants. PpCIPK1 transcription level was induced upon salt stress in P. patens. Using homologous recombination, we constructed PpCIPK1 knockout mutant lines (PpCIPK1 KO). Salt sensitivity analysis showed that independent PpCIPK1 KO plants exhibited severe growth inhibition and developmental deficiency of gametophytes under salt stress condition compared to that of wild-type P. patens (WT). Consistently, ionic homeostasis was disrupted in plants due to PpCIPK1 deletion, and high level of H2O2 was accumulated in PpCIPK1 KO than that in WT. Furthermore, PpCIPK1 functions in regulating photosynthetic activity in response to salt stress. Interestingly, we observed that PpCIPK1 could completely rescue the salt-sensitive phenotype of sos2-1 to WT level in Arabidopsis, indicating that AtSOS2 and PpCIPK1 are functionally conserved. In conclusion, our work provides evidence that PpCIPK1 participates in salt tolerance regulation in P. patens.


Asunto(s)
Bryopsida/fisiología , Proteínas de Plantas/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Plantas Tolerantes a la Sal/fisiología , Arabidopsis/genética , Proteínas de Arabidopsis , Bryopsida/genética , Regulación de la Expresión Génica de las Plantas , Técnicas de Inactivación de Genes , Genes de Plantas , Fotosíntesis , Fenómenos Fisiológicos de las Plantas , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/genética , Plantas Tolerantes a la Sal/genética , Alineación de Secuencia , Estrés Fisiológico , Transcriptoma
11.
Gene ; 781: 145538, 2021 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-33631245

RESUMEN

BACKGROUND: The genetics of binge-eating disorder (BED) is an emerging topic, with dopaminergic genes being implicated in its etiology due to the role that dopamine (DA) plays in food reward sensitivity and self-regulation of eating behavior. However, no study to date has examined if DA genes influence response to behavioral treatment of BED. OBJECTIVE: The primary objective of this study was to examine the ability of DA-associated polymorphisms to predict BED treatment response measured using binge frequency over 12 months. As secondary objectives, this study examined cross-sectional relationships between these polymorphisms and anthropometrics in women living with and without BED and obesity. METHODS: Women aged 18-64 years old were genotyped for the DA-related SNPs DRD2/ANKK1 Taq1A (rs1800497) and COMT (rs4680), as well as the DA-related uVNTRs DAT-1 (SLC6A3) and MAO-A. A multi-locus DA composite score was formed from these 4 polymorphisms using genotypes known to have a functional impact resulting in modified DA signaling. Binge frequency (Eating Disorder Examination - Interview) and body composition (Tanita BC-418) were assessed in a pre-post analysis to examine genetic predictors of treatment response in women living with obesity and BED. Secondary data analysis was conducted on a cross-sectional comparison of three groups of women enrolled in trial group treatment for BED: women living with obesity and BED (n = 72), obesity without BED (n = 27), and normal-weight without BED (n = 45). RESULTS: There were no significant genotype × time interactions related to anthropometrics or binge frequency for any individual DA genotypes, or to the composite score reflecting DA availability. At baseline, there were no significant between-group differences in frequencies of DA-related alleles, nor were there associations between genotypes and anthropometrics. CONCLUSIONS: Our study found no evidence to suggest that the DRD2/ANKK1 Taq1A, COMT, MAO-A, or DAT-1 polymorphisms are associated with response to behavioral intervention for BED as measured by changes in binge frequency. Future studies should examine a greater variety of dopaminergic polymorphisms, other candidate genes that target other neurotransmitter systems, as well as examine their impact on both behavioral and pharmacological-based treatment for BED.


Asunto(s)
Trastorno por Atracón/genética , Dopamina/genética , Polimorfismo Genético , Adolescente , Adulto , Trastorno por Atracón/metabolismo , Catecol O-Metiltransferasa/genética , Estudios Transversales , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Monoaminooxidasa/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores de Dopamina D2/genética , Adulto Joven
12.
Nat Immunol ; 22(2): 193-204, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33398181

RESUMEN

Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8+ effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8+ T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.


Asunto(s)
Linfocitos T CD8-positivos/enzimología , Neoplasias del Colon/enzimología , Metabolismo Energético , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/enzimología , Melanoma Experimental/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Citotoxicidad Inmunológica , Estabilidad de Enzimas , Femenino , Glucosafosfato Deshidrogenasa/metabolismo , Glucólisis , Hexoquinasa/genética , Hexoquinasa/metabolismo , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplante , Masculino , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones Endogámicos C57BL , Ratones Noqueados , NADP/metabolismo , Fenotipo , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Microambiente Tumoral
13.
Science ; 371(6524): 64-67, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33384372

RESUMEN

During cell division, kinetochores couple chromosomes to spindle microtubules. To protect against chromosome gain or loss, kinetochores lacking microtubule attachment locally catalyze association of the checkpoint proteins Cdc20 and Mad2, which is the key event in the formation of a diffusible checkpoint complex that prevents mitotic exit. We elucidated the mechanism of kinetochore-catalyzed Mad2-Cdc20 assembly with a probe that specifically monitors this assembly reaction at kinetochores in living cells. We found that catalysis occurs through a tripartite mechanism that includes localized delivery of Mad2 and Cdc20 substrates and two phosphorylation-dependent interactions that geometrically constrain their positions and prime Cdc20 for interaction with Mad2. These results reveal how unattached kinetochores create a signal that ensures genome integrity during cell division.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas Cdc20/metabolismo , Puntos de Control del Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Cinetocoros/metabolismo , Animales , Biocatálisis , Caenorhabditis elegans/citología , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Mitosis , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo
14.
Life Sci ; 270: 119084, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33482186

RESUMEN

AIMS: Polo-like kinase 2 (PLK2) belongs to a family of serine/threonine kinases, and it is involved in tumorigenesis. The present study aimed to explore the potential clinical significance of PLK2 in the development of gliomas. MAIN METHODS: Immunohistochemistry (IHC) was performed to detect the expression of PLK2 in glioma tissues. Cell proliferation and apoptosis were determined by Cell Counting Kit 8 (CCK8) and flow cytometry analysis, respectively. KEY FINDINGS: PLK2 expression gradually increased with the degree of glioma malignancy. High PLK2 expression was associated with a poor prognosis in glioma. Short hairpin RNAs targeting PLK2 (shPLK2) inhibited the viability and induced apoptosis of glioma cells, both in vitro and in vivo. Ring finger protein 180 (RNF180), an E3 ubiquitin ligase, interacted with PLK2 and induced the ubiquitination of PLK2. Overexpression of PLK2 in glioma cells significantly inhibited RNF180 upregulation-induced cell apoptosis. The expression level of RNF180 gradually decreased with the degree of glioma malignancy. SIGNIFICANCE: Knocking down of PLK2 may suppress the glioma development through cancer cell proliferation inhibition and cell apoptosis promotion. Furthermore, RNF180 may mediate the ubiquitination of PLK2. The present findings may help improve the clinical management of glioma in the future.


Asunto(s)
Glioma/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Adulto , Anciano , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Proliferación Celular/fisiología , China , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/genética , Interferencia de ARN/fisiología , ARN Interferente Pequeño/genética , Transducción de Señal/genética , Ubiquitina-Proteína Ligasas/metabolismo
15.
Life Sci ; 268: 119023, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33434534

RESUMEN

AIMS: Rhabdomyolysis-associated acute kidney injury (AKI) is life-threatening but effective treatments is lacking. Recently, fatty acid-binding protein 4 (FABP4) has been identified as a mediator of ischemic and toxic AKI through regulating endoplasmic reticulum (ER) stress in our previous studies. However, the role of FABP4 in rhabdomyolysis-induced AKI and extended organelle dysfunctions need to be explored and validated. MAIN METHODS: We firstly performed mRNA-seq and bioinformatic analysis to investigate the role of FABP4. The mouse model was established via injecting glycerol to FABP4 wild type (WT) and knockout (KO) mice. Blood biochemical, inflammatory and apoptotic parameters were measured and compared across groups. Representative pathways of ER stress and mitochondrial dysfunction were also detected and quantified. KEY FINDINGS: Comparing FABP4 WT and FABP4 KO model groups, FABP4 deficiency significantly attenuated renal dysfunction, by reducing serum creatinine (165.90 ± 15.61 µmol/L vs 35.5 ± 8.33 µmol/L, p < 0.0001) and blood urea nitrogen (89.78 ± 6.82 mmol/L vs 19.75 ± 5.97 mmol/L, p < 0.0001), and alleviating tubular injury scores. Inflammatory and apoptotic responses were alleviated by FABP4 genetic inhibition. Mechanistically, glycerol injection triggered ER stress characterized by activated IRE1, PERK, and ATF6 signaling pathways, and induced mitochondrial dysfunction supported by ultrastructural damage, energy metabolic derangement, and excessive mitochondrial fission (upregulated DRP1/downregulated OPA1). These two organelle dysfunctions were effectively relieved by FABP4 deficiency. SIGNIFICANCE: Taken together, genetic inhibition of FABP4 protected against rhabdomyolysis-induced AKI via reducing ER stress as well as mitochondrial dysfunction. FABP4 might act as a novel therapeutic target in rhabdomyolysis-induced AKI.


Asunto(s)
Lesión Renal Aguda/etiología , Estrés del Retículo Endoplásmico/genética , Proteínas de Unión a Ácidos Grasos/genética , Mitocondrias/patología , Rabdomiólisis/patología , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Lesión Renal Aguda/patología , Animales , Apoptosis/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Riñón/patología , Riñón/fisiología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/genética , Nefritis/genética , Nefritis/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo
16.
Nucleic Acids Res ; 49(3): 1411-1425, 2021 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-33450002

RESUMEN

DNA damage response is a fundamental mechanism to maintain genome stability. The ATR-WEE1 kinase module plays a central role in response to replication stress. Although the ATR-WEE1 pathway has been well studied in yeasts and animals, how ATR-WEE1 functions in plants remains unclear. Through a genetic screen for suppressors of the Arabidopsis atr mutant, we found that loss of function of PRL1, a core subunit of the evolutionarily conserved MAC complex involved in alternative splicing, suppresses the hypersensitivity of atr and wee1 to replication stress. Biochemical studies revealed that WEE1 directly interacts with and phosphorylates PRL1 at Serine 145, which promotes PRL1 ubiquitination and subsequent degradation. In line with the genetic and biochemical data, replication stress induces intron retention of cell cycle genes including CYCD1;1 and CYCD3;1, which is abolished in wee1 but restored in wee1 prl1. Remarkably, co-expressing the coding sequences of CYCD1;1 and CYCD3;1 partially restores the root length and HU response in wee1 prl1. These data suggested that the ATR-WEE1 module inhibits the MAC complex to regulate replication stress responses. Our study discovered PRL1 or the MAC complex as a key downstream regulator of the ATR-WEE1 module and revealed a novel cell cycle control mechanism.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/fisiología , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de Ciclo Celular/genética , Daño del ADN , Replicación del ADN , Genes cdc , Mutación , Proteínas Nucleares/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/fisiología , Empalme del ARN , Estrés Fisiológico , Supresión Genética , Ubiquitinación
17.
Nat Commun ; 12(1): 433, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33469010

RESUMEN

The poverty of disease resistance gene reservoirs limits the breeding of crops for durable resistance against evolutionary dynamic pathogens. Zymoseptoria tritici which causes Septoria tritici blotch (STB), represents one of the most genetically diverse and devastating wheat pathogens worldwide. No fully virulent Z. tritici isolates against synthetic wheats carrying the major resistant gene Stb16q have been identified. Here, we use comparative genomics, mutagenesis and complementation to identify Stb16q, which confers broad-spectrum resistance against Z. tritici. The Stb16q gene encodes a plasma membrane cysteine-rich receptor-like kinase that was recently introduced into cultivated wheat and which considerably slows penetration and intercellular growth of the pathogen.


Asunto(s)
Productos Agrícolas/genética , Resistencia a la Enfermedad/genética , Proteínas de Plantas/genética , Proteínas Serina-Treonina Quinasas/genética , Triticum/genética , Alelos , Ascomicetos/patogenicidad , Membrana Celular/enzimología , Productos Agrícolas/microbiología , Genes de Plantas/genética , Fitomejoramiento/métodos , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/microbiología , Semillas/genética , Triticum/enzimología , Triticum/microbiología
18.
Nat Commun ; 12(1): 617, 2021 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-33504784

RESUMEN

The blood-brain barrier (BBB) is critical for neural function. We report here circadian regulation of the BBB in mammals. Efflux of xenobiotics by the BBB oscillates in mice, with highest levels during the active phase and lowest during the resting phase. This oscillation is abrogated in circadian clock mutants. To elucidate mechanisms of circadian regulation, we profiled the transcriptome of brain endothelial cells; interestingly, we detected limited circadian regulation of transcription, with no evident oscillations in efflux transporters. We recapitulated the cycling of xenobiotic efflux using a human microvascular endothelial cell line to find that the molecular clock drives cycling of intracellular magnesium through transcriptional regulation of TRPM7, which appears to contribute to the rhythm in efflux. Our findings suggest that considering circadian regulation may be important when therapeutically targeting efflux transporter substrates to the CNS.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Relojes Circadianos , Xenobióticos/metabolismo , Factores de Transcripción ARNTL/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Transporte Biológico , Línea Celular , Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Humanos , Magnesio/metabolismo , Ratones Endogámicos C57BL , Modelos Biológicos , Permeabilidad , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especificidad por Sustrato , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo
19.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33477764

RESUMEN

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas de Ciclo Celular/antagonistas & inhibidores , Rosácea/tratamiento farmacológico , Transactivadores/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Ciclo Celular/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Proteínas Serina-Treonina Quinasas/genética , Rosácea/genética , Rosácea/patología , Transducción de Señal/efectos de los fármacos , Piel/efectos de los fármacos , Piel/patología , Transactivadores/genética
20.
J Cancer Res Clin Oncol ; 147(4): 1049-1064, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33387038

RESUMEN

PURPOSE: Lung adenocarcinoma (LUAD) accounts for approximately half of patients in lung cancer. Cancer-associated fibroblasts (CAFs) are the major component in the tumor microenvironment (TME). Targeting CAFs is a promising therapeutic strategy for cancer treatment. However, therapeutic targets of CAFs in LUAD remains largely unclear. METHODS: Seven CAFs and nine normal fibroblasts (NFs) were isolated from tumor and paratumor tissues of LUAD patients undergoing surgery, respectively. RNA-seq and bioinformatics analysis were performed to identify the differentially expressed genes (DEGs) and their functions in CAFs compared with NFs. DEGs of ten overlaying were obtained from RNA-seq, our previously reported lncRNA microarray and public datasets (E-MTAB-6149, E-MTAB-6653) and validated by RT-qPCR. Nik-related kinase (NRK) was further validated by RT-qPCR, immunofluorescence (IF), Western Blot (WB) in vitro, and in Cancer Cell Line Encyclopedia (CCLE) database. Survival analysis was performed on Kaplan-Meier plotter. RESULTS: A total of 1799 DEGs were identified, including 650 upregulated DEGs and 1149 downregulated DEGs. The upregulated and downregulated DEGs were mostly enriched in extracellular matrix (ECM) functions and in glycolysis/gluconeogenesis pathways. Interestingly, NRK was the most significantly upregulated overlaying DEGs which was rarely associated with CAFs before. NRK was predominantly expressed in CAFs, but weakly expressed in NFs, normal lung bronchial epithelial cell line BEAS-2B, LUAD cell lines A549 and H1299, as well as in the majority of 191 lung cancer cell lines including LUAD. Moreover, elevated NRK predicted poor survival in LUAD patients. CONCLUSION: Here, we first report that NRK is significantly elevated in LUAD-associated CAFs and may function as a promising therapeutic target for cancer combination treatment. Besides, modulation of ECM and glycolysis/gluconeogenesis pathways may be an efficient approach to alter CAFs functionality in LUAD.


Asunto(s)
Adenocarcinoma del Pulmón/patología , Biomarcadores de Tumor/metabolismo , Fibroblastos Asociados al Cáncer/patología , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Pulmonares/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Microambiente Tumoral , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Biomarcadores de Tumor/genética , Fibroblastos Asociados al Cáncer/metabolismo , Femenino , Estudios de Seguimiento , Redes Reguladoras de Genes , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Mapas de Interacción de Proteínas , Proteínas Serina-Treonina Quinasas/genética , RNA-Seq , Tasa de Supervivencia , Células Tumorales Cultivadas
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