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1.
Antioxid Redox Signal ; 40(10-12): 595-597, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38386512

RESUMO

Recent studies have provided evidence for the direct binding of thioredoxin-1 (TRX1) to a component of inflammasome complex NLR family pyrin domain containing 1 (NLRP-1). This interaction suggests a potential role for TRX1 in the regulation of the NLRP-1 inflammasome. Furthermore, the NLRP-3 inflammasome is known to bind TRX1 and its inhibitor, TRX-binding protein-2/TRX-interacting protein/vitamin D3 upregulated protein-1 (TBP2/TXNIP/VDUP-1). This binding forms a redox-sensitive complex, termed the "Redoxisome," as described previously. However, the specific functions of NLRP-1 within the redoxisome complex remain undefined. Antioxid. Redox Signal. 40, 595-597.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oxirredução , Tiorredoxinas/metabolismo
2.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360561

RESUMO

Pre-mRNA splicing is an essential process for gene expression in higher eukaryotes, which requires a high order of accuracy. Mutations in splicing factors or regulatory elements in pre-mRNAs often result in many human diseases. Myelodysplastic syndrome (MDS) is a heterogeneous group of chronic myeloid neoplasms characterized by many symptoms and a high risk of progression to acute myeloid leukemia. Recent findings indicate that mutations in splicing factors represent a novel class of driver mutations in human cancers and affect about 50% of Myelodysplastic syndrome (MDS) patients. Somatic mutations in MDS patients are frequently found in genes SF3B1, SRSF2, U2AF1, and ZRSR2. Interestingly, they are involved in the recognition of 3' splice sites and exons. It has been reported that mutations in these splicing regulators result in aberrant splicing of many genes. In this review article, we first describe molecular mechanism of pre-mRNA splicing as an introduction and mainly focus on those four splicing factors to describe their mutations and their associated aberrant splicing patterns.


Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Precursores de RNA/genética , Fatores de Processamento de RNA/genética , Splicing de RNA , Humanos
3.
Biochem Biophys Res Commun ; 526(4): 973-977, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32295714

RESUMO

Alternative splicing of the pyruvate kinase M (PKM) pre-mRNA generates two isoforms, PKM1 and PKM2. PKM catalyzes the conversion of phosphoenol-pyruvate to pyruvate in glycolytic pathway. PKM1 exist as a stable tetramer that is at an active enzyme state, while PKM2 is in equilibrium among monomer, dimer and tetramer under the regulation of its allosteric activators. Many cancer cells show the feature of higher glucose uptake and lactate production in spite of oxygen availability, which is known as the Warburg effect. PKM2 is upregulated in most cancer types and the inactive PKM2 lead to the cancer metabolism. In addition, dimeric PKM2 induces its nuclear translocation through posttranslational modification and acts as a transcriptional co-activator for the expression of oncogenes. Therefore, it is important to elucidate mechanisms for modulation of an active or inactive state of PKM2, namely the tetramer-to-dimer-transition. The definitive difference between PKM1 and PKM2 is to constitutively form tetramer or not in the cytoplasm, which is ascribed to 22 amino acids derived from exon 9 (PKM1) or exon 10 (PKM2). In this study, we generated 22 different PKM1-mimetic point mutants of PKM2, and demonstrated that replacement of cysteine424 residue of PKM2 with leucine424 conserved in PKM1 (C424L) promote its tetramerization. PKM2(C424L) formed a tetramer without allosteric activator, and escaped the inhibitory effects by oxidative stress, like PKM1. Our findings intensely suggest that C424 or L424 determines the different catalytic and modulatory properties between PKM splicing isoforms.


Assuntos
Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Cisteína/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Estresse Oxidativo , Multimerização Proteica , Hormônios Tireóideos/química , Hormônios Tireóideos/metabolismo , Sequência de Aminoácidos , Diamida/farmacologia , Células HeLa , Humanos , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutação/genética , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas de Ligação a Hormônio da Tireoide
4.
Genes Cells ; 25(5): 327-333, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32050040

RESUMO

SRSF4 is one of the members of serine-/arginine (SR)-rich protein family involved in both constitutive and alternative splicing. SRSF4 is localized in the nucleus with speckled pattern, but its nuclear localization signal was not determined. Here, we have identified nuclear localization signals (NLSs) of SRSF4 by using a pyruvate kinase fusion system. As expected, arginine-/serine (RS)-rich domain of SRSF4 confers nuclear localization activity when it is fused to PK protein. We then further delineated the minimum sequences for nuclear localization in RS domain of SRSF4. Surprisingly, RS-rich region does not always have a nuclear localization activity. In addition, basic amino acid stretches that resemble to classical-type NLSs were identified. These results strongly suggest that SRSF4 protein uses two different nuclear import pathways with multiple NLSs in RS domain.


Assuntos
Núcleo Celular/genética , Sinais de Localização Nuclear/genética , Fatores de Processamento de Serina-Arginina/genética , Sequência de Aminoácidos , Núcleo Celular/metabolismo , Humanos , Sinais de Localização Nuclear/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo
5.
Front Genet ; 10: 338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040863

RESUMO

Serine/arginine-rich splicing factor 2 (SRSF2) is a member of the SR protein family that is involved in both constitutive and alternative mRNA splicing. Mutations in SRSF2 gene are frequently reported in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). It is imperative to understand how these mutations affect SRSF2-mediated splicing and cause MDS. In this study, we characterized MDS-associated SRSF2 mutants (P95H, P95L, and P95R). We found that those mutants and wild-type SRSF2 proteins showed nuclear localization in HeLa cells. In vitro splicing reaction also revealed that mutant proteins associated with both precursor and spliced mRNAs, suggesting that the mutants directly participate in splicing. We established the human myeloid leukemia K562 cell lines that stably expressed myc-tagged wild-type or mutant SRSF2 proteins, and then performed RNA-sequence to analyze the splicing pattern of each cell line. The results revealed that both wild-type and mutants affected splicing of approximately 3,000 genes. Although splice site sequences adjacent to the affected exons showed no significant difference compared to the total exons, exonic motif analyses with both inclusion- and exclusion-enhanced exons demonstrated that wild-type and mutants have different binding sequences in exons. These results indicate that mutations of SRSF2 in MDS change binding properties of SRSF2 to exonic motifs and this causes aberrant splicing.

6.
Bioorg Med Chem ; 23(15): 4434-4441, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26145823

RESUMO

Dysregulation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has been demonstrated in several pathological conditions, including Alzheimer's disease and cancer progression. It has been recently reported that a gain of function-mutation in the human DYRK1B gene exacerbates metabolic syndrome by enhancing obesity. In the previous study, we developed an inhibitor of DYRK family kinases (INDY) and demonstrated that INDY suppresses the pathological phenotypes induced by overexpression of DYRK1A or DYRK1B in cellular and animal models. In this study, we designed and synthesized a novel inhibitor of DYRK family kinases based on the crystal structure of the DYRK1A/INDY complex by replacing the phenol group of INDY with dibenzofuran to produce a derivative, named BINDY. This compound exhibited potent and selective inhibitory activity toward DYRK family kinases in an in vitro assay. Furthermore, treatment of 3T3-L1 pre-adipocytes with BINDY hampered adipogenesis by suppressing gene expression of the critical transcription factors PPARγ and C/EBPα. This study indicates the possibility of BINDY as a potential drug for metabolic syndrome.


Assuntos
Benzofuranos/síntese química , Benzotiazóis/síntese química , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Benzofuranos/química , Benzofuranos/toxicidade , Benzotiazóis/química , Benzotiazóis/toxicidade , Sítios de Ligação , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Humanos , Camundongos , Simulação de Acoplamento Molecular , PPAR gama/genética , PPAR gama/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Quinases Dyrk
7.
Int J Mol Sci ; 16(2): 3705-21, 2015 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-25671812

RESUMO

In eukaryotes, pre-mRNA splicing is an essential step for gene expression. We have been analyzing post-splicing intron turnover steps in higher eukaryotes. Here, we report protein interaction between human Debranching enzyme 1 (hDbr1) and several factors found in the Intron Large (IL) complex, which is an intermediate complex of the intron degradation pathway. The hDbr1 protein specifically interacts with xeroderma pigmentosum, complementeation group A (XPA)-binding protein 2 (Xab2). We also attempted to identify specific interactors of hDbr1. Co-immunoprecipitation experiments followed by mass spectrometry analysis identified a novel protein as one of the specific interactors of hDbr1. This protein is well conserved among many species and shows the highest similarity to yeast Drn1, so it is designated as human Dbr1 associated ribonuclease 1 (hDrn1). hDrn1 directly interacts with hDbr1 through protein-protein interaction. Furthermore, hDrn1 shuttles between the nucleus and the cytoplasm, as hDbr1 protein does. These findings suggest that hDrn1 has roles in both the nucleus and the cytoplasm, which are highly likely to involve hDbr1.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , RNA Nucleotidiltransferases/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Técnicas de Cocultura , Células HEK293 , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Células NIH 3T3 , Mapas de Interação de Proteínas , RNA Nucleotidiltransferases/genética , Fatores de Processamento de RNA , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
8.
Front Immunol ; 4: 514, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24409188

RESUMO

During the past few decades, it has been widely recognized that Reduction-Oxidation (redox) responses occurring at the intra- and extra-cellular levels are one of most important biological phenomena and dysregulated redox responses are involved in the initiation and progression of multiple diseases. Thioredoxin1 (Trx1) and Thioredoxin2 (Trx2), mainly located in the cytoplasm and mitochondria, respectively, are ubiquitously expressed in variety of cells and control cellular reactive oxygen species by reducing the disulfides into thiol groups. Thioredoxin interacting protein (Txnip/thioredoxin binding protein-2/vitamin D3 upregulated protein) directly binds to Trx1 and Trx2 (Trx) and inhibit the reducing activity of Trx through their disulfide exchange. Recent studies have revealed that Trx1 and Txnip are involved in some critical redox-dependent signal pathways including NLRP-3 inflammasome activation in a redox-dependent manner. Therefore, Trx/Txnip, a redox-sensitive signaling complex is a regulator of cellular redox status and has emerged as a key component in the link between redox regulation and the pathogenesis of diseases. Here, we review the novel functional concept of the redox-related protein complex, named "Redoxisome," consisting of Trx/Txnip, as a critical regulator for intra- and extra-cellular redox signaling, involved in the pathogenesis of various diseases such as cancer, autoimmune disease, and diabetes.

9.
PLoS One ; 7(6): e39900, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22768160

RESUMO

BACKGROUND: Transforming growth factor beta (TGF-ß) has critical roles in regulating cell growth, differentiation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) of various cancer cells. TGF-ß-induced EMT is an important step during carcinoma progression to invasion state. Thioredoxin binding protein-2 (TBP-2, also called Txnip or VDUP1) is downregulated in various types of human cancer, and its deficiency results in the earlier onset of cancer. However, it remains unclear how TBP-2 suppresses the invasion and metastasis of cancer. PRINCIPAL FINDINGS: In this study, we demonstrated that TBP-2 deficiency increases the transcriptional activity in response to TGF-ß and also enhances TGF-ß-induced Smad2 phosphorylation levels. Knockdown of TBP-2 augmented the TGF-ß-responsive expression of Snail and Slug, transcriptional factors related to TGF-ß-mediated induction of EMT, and promoted TGF-ß-induced spindle-like morphology consistent with the depletion of E-Cadherin in A549 cells. CONCLUSIONS/SIGNIFICANCE: Our results indicate that TBP-2 deficiency enhances TGF-ß signaling and promotes TGF-ß-induced EMT. The control of TGF-ß-induced EMT is critical for the inhibition of the invasion and metastasis. Thus TBP-2, as a novel regulatory molecule of TGF-ß signaling, is likely to be a prognostic indicator or a potential therapeutic target for preventing tumor progression.


Assuntos
Proteínas de Transporte/metabolismo , Transição Epitelial-Mesenquimal , Transdução de Sinais , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Caderinas/metabolismo , Forma Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Smad2/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/metabolismo , Transcrição Gênica/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia
10.
J Clin Biochem Nutr ; 50(1): 23-34, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22247597

RESUMO

Thioredoxin binding protein -2/ thioredoxin interacting protein is an α-arrestin protein that has attracted much attention as a multifunctional regulator. Thioredoxin binding protein -2 expression is downregulated in tumor cells and the level of thioredoxin binding protein is correlated with clinical stage of cancer. Mice with mutations or knockout of the thioredoxin binding protein -2 gene are much more susceptible to carcinogenesis than wild-type mice, indicating a role for thioredoxin binding protein -2 in cancer suppression. Studies have also revealed roles for thioredoxin binding protein -2 in metabolic control. Enhancement of thioredoxin binding protein -2 expression causes impairment of insulin sensitivity and glucose-induced insulin secretion, and ß-cell apoptosis. These changes are important characteristics of type 2 diabetes mellitus. Thioredoxin binding protein -2 regulates transcription of metabolic regulating genes. Thioredoxin binding protein -2-like inducible membrane protein/ arrestin domain containing 3 regulates endocytosis of receptors such as the ß(2)-adrenergic receptor. The α-arrestin family possesses PPXY motifs and may function as an adaptor/scaffold for NEDD family ubiquitin ligases. Elucidation of the molecular mechanisms of α-arrestin proteins would provide a new pharmacological basis for developing approaches against cancer and type 2 diabetes mellitus.

11.
Nat Commun ; 1: 127, 2010 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-21119640

RESUMO

Type 2 diabetes mellitus (T2DM) is characterized by defects in both insulin sensitivity and glucose-stimulated insulin secretion (GSIS) and is often accompanied by obesity. In this study, we show that disruption of thioredoxin binding protein-2 (TBP-2, also called Txnip) in obese mice (ob/ob) dramatically improves hyperglycaemia and glucose intolerance, without affecting obesity or adipocytokine concentrations. TBP-2-deficient ob/ob mice exhibited enhanced insulin sensitivity with activated insulin receptor substrate-1/Akt signalling in skeletal muscle and GSIS in islets compared with ob/ob mice. The elevation of uncoupling protein-2 (UCP-2) expression in ob/ob islets was downregulated by TBP-2 deficiency. TBP-2 overexpression suppressed glucose-induced adenosine triphosphate production, Ca(2+) influx and GSIS. In ß-cells, TBP-2 enhanced the expression level and transcriptional activity of UCP-2 by recruitment of peroxisome proliferator-activated receptor-γ co-activator-1α to the UCP-2 promoter. Thus, TBP-2 is a key regulatory molecule of both insulin sensitivity and GSIS in diabetes, raising the possibility that inhibition of TBP-2 may be a novel therapeutic approach for T2DM.

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