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1.
J Biol Chem ; 295(12): 4049-4063, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32005663

RESUMO

Cellular senescence is terminal cell cycle arrest that represents a prominent response to numerous anticancer therapies. The oncogene inhibitor of the apoptosis-stimulating protein of p53 (iASPP) plays essential roles in regulating cellular drug response by inhibiting apoptosis. However, whether or not it regulates chemotherapy-induced senescence (TIS) in cancer cells remains unclear. Here, using two commonly used cancer cell lines, HCT 116 and MCF-7, along with the xenograft mouse model, we found that iASPP inhibits senescence and also influences the senescence-associated secretory phenotype (SASP), which confers anticancer drug resistance independently of apoptosis. Mechanistically, iASPP is transcriptionally elevated by the p65 subunit of NF-κB in senescent cells and then translocates to the nucleus, where it binds p53 and NF-κBp65. This binding inhibits their transcriptional activities toward p21 and the key SASP factors interleukin (IL)-6/IL-8, respectively, and subsequently prevents senescence. Of note, we observed that iASPP knockdown sensitizes apoptosis-resistant cancers to doxorubicin treatment by promoting senescence both in vitro and in vivo We conclude that iASPP integrates the NF-κBp65- and p53-signaling pathways and thereby regulates cell fate in response to TIS, leading to chemotherapy resistance. These findings suggest that iASPP inhibition might be a strategy that could help restore senescence in cancer cells and improve outcomes of chemotherapy-based therapies.

2.
Cell Death Differ ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31700144

RESUMO

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) play important roles in human diseases, including cancer; however, only a few of them have been experimentally validated and functionally annotated. Here, we identify a novel lncRNA that we term HITT (HIF-1α inhibitor at translation level). HITT is commonly decreased in multiple human cancers. Decreased HITT is associated with advanced stages of colon cancer. Restoration of the expression of HITT in cancer cells inhibits angiogenesis and tumor growth in vivo in an HIF-1α-dependent manner. Further study reveals that HITT inhibits HIF-1α expression, mainly by interfering with its translation. Mechanically, HITT titrates away YB-1 from the 5'-UTR of HIF-1α mRNA via a high-stringency YB-1-binding motif. The reverse correlation between HITT and HIF-1α expression is further validated in human colon cancer tissues. Moreover, HITT is one of the most altered lncRNAs upon the hypoxic switch and HITT downregulation is required for hypoxia-induced HIF-1α expression. We further demonstrate that HITT and HIF-1α form an autoregulatory feedback loop where HIF-1α destabilizes HITT by inducing MiR-205, which directly targets HITT for degradation. Together, these results expand our understanding of the cancer-associated functions of lncRNAs, highlighting the HITT-HIF-1α axis as constituting an additional layer of regulation of angiogenesis and tumor growth, with potential implications for therapeutic targeting.

3.
Biomolecules ; 9(3)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884740

RESUMO

Phosphorylation of inositol phospholipids by the family of phosphoinositide 3-kinases (PI3Ks) is crucial in controlling membrane lipid composition and regulating a wide range of intracellular processes, which include signal transduction and vesicular trafficking. In spite of the extensive knowledge on class I PI3Ks, recent advances in the study of the three class II PI3Ks (PIK3C2A, PIK3C2B and PIK3C2G) reveal their distinct and non-overlapping cellular roles and localizations. By finely tuning membrane lipid composition in time and space among different cellular compartments, this class of enzymes controls many cellular processes, such as proliferation, survival and migration. This review focuses on the recent developments regarding the coordination of membrane trafficking and intracellular signaling of class II PI3Ks through the confined phosphorylation of inositol phospholipids.


Assuntos
Membrana Celular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis/metabolismo , Transdução de Sinais , Animais , Membrana Celular/química , Humanos , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositóis/química , Fosforilação , Transporte Proteico
4.
Cancer Lett ; 432: 121-131, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-29890207

RESUMO

Renal cell carcinoma (RCC) is highly resistant to chemotherapies. The lack of efficacious treatment for metastatic RCC has led to a poor 5-year survival rate. Here, we found that Apoptosis-stimulating protein of p53-2(ASPP2) was frequently decreased in primary RCC tissues in comparison with non-tumoural kidney controls. Decreased ASPP2 was correlated with high grades and poor outcomes of RCC. Further studies revealed that ASPP2 downregulation promoted EMT and increased resistance to 5-Fluorouracil (5-FU)-induced apoptosis. To this end, the regulatory mechanisms of ASPP2 were further explored. Our data revealed that ASPP2 was inhibited by histone deacetylatlase 1 (HDAC1), which acted by preventing the binding between transcription factor (E2F1) and the ASPP2 promoter. Of particular importance, HDAC1 inhibitor vorinostat restored ASPP2 transcription and produced a synergistic effect with 5-FU in elevating ASPP2, promoting apoptosis and inhibiting EMT in both in vitro and in vivo RCC models. In summary, our data not only highlight an important role of ASPP2 in RCC progression and drug resistance, but also reveal new regulatory mechanisms of ASPP2, which provides important insights into novel treatment strategies by targeting ASPP2 dysregulation in RCC.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma de Células Renais/patologia , Movimento Celular , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Fluoruracila/farmacologia , Histona Desacetilase 1/metabolismo , Animais , Antimetabólitos Antineoplásicos , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1/genética , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Células Tumorais Cultivadas , Cicatrização , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Cell ; 32(5): 561-573.e6, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29033244

RESUMO

Reactive oxygen species (ROS) have emerged as important signaling molecules that play crucial roles in carcinogenesis and cytotoxic responses. Nrf2 is the master regulator of ROS balance. Thus, uncovering mechanisms of Nrf2 regulation is important for the development of alternative treatment strategies for cancers. Here, we demonstrate that iASPP, a known p53 inhibitor, lowers ROS independently of p53. Mechanistically, iASPP competes with Nrf2 for Keap1 binding via a DLT motif, leading to decreased Nrf2 ubiquitination and increased Nrf2 accumulation, nuclear translocation, and antioxidative transactivation. This iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance both in vitro and in vivo. Thus, iASPP is an antioxidative factor and represents a promising target to improve cancer treatment, regardless of p53 status.


Assuntos
Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Repressoras/metabolismo , Antioxidantes/metabolismo , Western Blotting , Linhagem Celular Tumoral , Células HCT116 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Ligação Proteica , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
6.
ACS Appl Mater Interfaces ; 9(40): 34687-34695, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-28901736

RESUMO

Wearable pressure sensors have attracted increasing attention for biomechanical monitoring due to their portability and flexibility. Although great advances have been made, there are no facile methods to produce sensors with good performance. Here, we present a simple method for manufacturing flexible and self-powered piezoelectric sensors based on LiNbO3 (LN) particles. The LN particles are dispersed in polypropylene (PP) doped with multiwalled carbon nanotubes (MWCNTs) by hot pressing (200 °C) to form a flexible LN/MWCNT/PP piezoelectric composite film (PCF) sensor. This cost-effective sensor has high sensitivity (8 Pa), fast response time (ca. 40 ms), and long-term stability (>3000 cycles). Measurements of pressure changes from peripheral arteries demonstrate the applicability of the LN/MWCNT/PP PCF sensor to biomechanical monitoring as well as its potential for biomechanics-related clinical diagnosis and forecasting.


Assuntos
Nióbio/química , Óxidos/química , Nanotubos de Carbono , Pressão
7.
Int J Cancer ; 141(7): 1422-1433, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28656647

RESUMO

Inactivation of p53 has been shown to correlate with drug resistance in tumors. However, in clear cell renal cell carcinoma (ccRCC), p53 is rarely mutated, yet the tumors remain highly insensitive to the conventional chemotherapeutic drugs. The underlying mechanisms responsible for the non-genetic p53 inactivation remain obscure. Here, we report, for the first time, that Apoptosis Stimulating of P53 Protein 1 (ASPP1) was remarkably downregulated at both mRNA (about 3.9-fold) and protein (about 4.9-fold) levels in ccRCC human specimens in comparison with the paired normal controls. In addition, lower ASPP1 was closely related to the higher grade of tumors and shorter life expectancy of ccRCC patients, both with p < 0.001. We also find that CpG island hypermethylation at promoter region contributed to the suppression of ASPP1 expression in ccRCC that contained relatively low levels of ASPP1. Further functional studies demonstrated that forced expression ASPP1 not only significantly inhibited the growth rate of ccRCC, but also promoted sensitivity of ccRCC to the conventional chemotherapeutic drug 5-fluorouracil (5-FU)-induced apoptosis. Moreover, ASPP1 expression was accompanied with the apoptosis-prone alterations of p53 targets expression and p53 target PIG3 luciferase reporter activation. In contrast, ASPP1 knockdown promoted cell growth and prevent 5-FU-induced p53 activation and apoptosis. In conclusion, our results suggest that ASPP1 silencing is one of dominate mechanisms in inhibiting wild type p53 in ccRCC. ASPP1, therefore, may be potentially used as a promising biomarker for prognosis and therapeutic intervention in ccRCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Ilhas de CpG , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Proteínas Reguladoras de Apoptose/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Linhagem Celular Tumoral , Metilação de DNA , Regulação para Baixo , Epigênese Genética , Feminino , Fluoruracila/farmacologia , Inativação Gênica , Genes p53 , Humanos , Rim/metabolismo , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Ativação Transcricional , Transplante Heterólogo
8.
Sci Rep ; 7: 45065, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28332612

RESUMO

The world faces severe environmental, human and ecological problems when major oil spills and organic discharges are released into the environment. And so it is imperative to develop tools and high performance innovative materials that can efficiently absorb these organic discharges. Furthermore, green, facile methods to produce these advanced materials are also needed. In this paper, we demonstrate a novel porous supersponge based on melamine coated with hBN. This superhydrophobic sponge (with a contact angle >150°) exhibits excellent absorption performance for oils and organic solvents, including good selectivity, high capacity (up to 175 g·g-1) and extraordinary recyclability (less than 20% decline after 30 cycles of absorption/squeezing). The synthetic procedure required only ultrasonication and immersion of the sponge in aqueous hBN solution, being a green, cost-effective and scalable production methodology. By virtue of the straightforward and cost-effective fabrication method, along with the excellent absorption performance, hBN-decorated sponges have great promise for real world practical application in the field of oil spills and organic leakage cleanup.


Assuntos
Compostos de Boro/química , Poríferos/química , Poríferos/metabolismo , Animais , Interações Hidrofóbicas e Hidrofílicas , Microscopia de Força Atômica , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Difração de Raios X
9.
Front Plant Sci ; 7: 544, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27148348

RESUMO

N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are involved in plant resistance; however, the role of SYP71 in the regulation of plant-pathogen interactions is not well known. In this study, we characterized a plant-specific SNARE in wheat, TaSYP71, which contains a Qc-SNARE domain. Three homologs are localized on chromosome 1AL, 1BL, and 1DL. Using Agrobacterium-mediated transient expression, TaSYP71 was localized to the plasma membrane in Nicotiana benthamiana. Quantitative real-time PCR assays revealed that TaSYP71 homologs was induced by NaCl, H2O2 stress and infection by virulent and avirulent Puccinia striiformis f. sp. tritici (Pst) isolates. Heterologous expression of TaSYP71 in Schizosaccharomyces pombe elevated tolerance to H2O2. Meanwhile, H2O2 scavenging gene (TaCAT) was downregulated in TaSYP71 silenced plants treated by H2O2 compared to that in control, which indicated that TaSYP71 enhanced tolerance to H2O2 stress possibly by influencing the expression of TaCAT to remove the excessive H2O2 accumulation. When TaSYP71 homologs were all silenced in wheat by the virus-induced gene silencing system, wheat plants were more susceptible to Pst, with larger infection area and more haustoria number, but the necrotic area of wheat mesophyll cells were larger, one possible explanation that minor contribution of resistance to Pst was insufficient to hinder pathogen extension when TaSYP71 were silenced, and the necrotic area was enlarged accompanied with the pathogen growth. Of course, later cell death could not be excluded. In addition, the expression of pathogenesis-related genes were down-regulated in TaSYP71 silenced wheat plants. These results together suggest that TaSYP71 play a positive role in wheat defense against Pst.

10.
Sci Rep ; 6: 26946, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27230563

RESUMO

Metacaspase orthologs are conserved in fungi, protozoa and plants, however, their roles in plant disease resistance are largely unknown. In this study, we identified a Triticum aestivum metacaspase gene, TaMCA1, with three copies located on chromosomes 1A, 1B and 1D. The TaMCA1 protein contained typical structural features of type I metacaspases domains, including an N-terminal pro-domain. Transient expression analyses indicated that TaMCA1 was localized in cytosol and mitochondria. TaMCA1 exhibited no caspase-1 activity in vitro, but was able to inhibit cell death in tobacco and wheat leaves induced by the mouse Bax gene. In addition, the expression level of TaMCA1 was up-regulated following challenge with the Puccinia striiformis f. sp. tritici (Pst). Knockdown of TaMCA1 via virus-induced gene silencing (VIGS) enhanced plant disease resistance to Pst, and the accumulation of hydrogen peroxide (H2O2). Further study showed that TaMCA1 decreased yeast cell resistance similar to the function of yeast metacaspase, and there was no interaction between TaMCA1 and TaLSD1. Based on these combined results, we speculate that TaMCA1, a regulator of cell death, is important during the compatible interaction of wheat and Pst.


Assuntos
Basidiomycota/fisiologia , Caspases/genética , Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Patógeno , Proteínas de Plantas/genética , Triticum/genética , Animais , Basidiomycota/patogenicidade , Caspases/deficiência , Cromossomos de Plantas/química , Citosol/enzimologia , Citosol/microbiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Resistência à Doença , Dosagem de Genes , Técnicas de Silenciamento de Genes , Camundongos , Mitocôndrias/enzimologia , Mitocôndrias/genética , Mitocôndrias/microbiologia , Células Vegetais/enzimologia , Células Vegetais/microbiologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Folhas de Planta/enzimologia , Folhas de Planta/genética , Folhas de Planta/microbiologia , Proteínas de Plantas/metabolismo , Vírus de Plantas/genética , Vírus de Plantas/metabolismo , Tabaco/enzimologia , Tabaco/genética , Tabaco/microbiologia , Transgenes , Triticum/enzimologia , Triticum/microbiologia , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
11.
Plant Physiol Biochem ; 68: 90-5, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23665893

RESUMO

Plants live in a complex environment, exposed to stresses, such as unsuitable climates, pests and pathogenic microorganisms. Pathogens are one of the most serious factors that threaten plant growth. Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive diseases worldwide. Virus-induced gene silencing (VIGS) is a popular tool for the functional analysis of wheat genes, generating abundant small RNAs (sRNAs). sRNAs are key components in gene regulatory networks, silencing corresponding genes at the post-transcriptional level. In this study, we transduced pri-tae-miR159a into plant tissues using the barley stripe mosaic virus (BSMV) system, and demonstrated that vsiRNAs were generated from the same miRNAs generating sites of pri-tae-miR159a, with the function of Dicer RNase III-like classes of endonucleases (DCL4). In addition, the accumulation of vsiRNAs in wheat leaves challenged with Pst Chinese yellow rust 23 (CYR23), resulted in a resistant phenotype, and in the compatible interaction, the sporation of Pst was limited. Whereas, infection with a control construct had no effect on the resistance or susceptibility. The results of the histological observation also supported these phenotype changes. Interestingly, vsiRNAs were also involved in the interactions between wheat and Pst through the tae-miR159-mediated regulation of taMyb3 expression. Moreover, these results also supported the speculation that vsiRNAs were generated from the same sites of pri-tae-miR159a. These studies indicated that vsiRNAs from miRNAs generating sites of pri-tae-miR159a based on the BSMV system play positive roles in the wheat response to Pst through the regulation of taMyb3 expression.


Assuntos
Basidiomycota/patogenicidade , Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Patógeno/genética , MicroRNAs/genética , Vírus do Mosaico/genética , Proteínas de Plantas/genética , Triticum/genética , Triticum/microbiologia , Resistência à Doença/genética , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Proteínas de Plantas/metabolismo , Ribonuclease III/genética , Ribonuclease III/metabolismo
12.
Analyst ; 137(21): 5051-6, 2012 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-22973573

RESUMO

With the development of material science and the practical needs of the polymer industry, rapid characterization of synthetic polymers using mass spectrometry is of sustainable interest. Herein a new method for characterizing synthetic polymers using thermal-assisted atmospheric pressure glow discharge mass spectrometry (TA-APGD-MS) is established. After illustration of the mechanism of ion formation, typical polymer samples such as polystyrene (PS), polyoxymethylene (POM) and poly (butanediol succinate) (PBS) were directly characterized at the molecular level using TA-APGD-MS. The thermal degradation products of synthetic polymers including monomer units and/or other fragments were rapidly detected by tandem mass spectrometry, providing rich information about the chemical composition for the structural characterization of homo- and co-polymers. The result suggests that TA-APGD-MS allows direct and rapid analysis of both synthetic homo-polymers and co-polymers under ambient conditions without any sample pretreatment. This method features high throughput, high sensitivity and rich information, showing promising applications in polymer science.


Assuntos
Pressão Atmosférica , Espectrometria de Massas/métodos , Polímeros/química , Temperatura Ambiente , Ar , Polímeros/síntese química
13.
J Phys Chem A ; 114(7): 2697-700, 2010 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-20121221

RESUMO

The mechanism of ethylene insertions into eight tertiary diamine/n-butyllithium complexes has been studied at the BLYP/DNP level. In contrast to the cationic coordination polymerization in which a strong coordination complex between ethylene and the metal center is formed prior to ethylene insertion, there is only a weak van der Waals complex between ethylene and tertiary diamine/n-butyllithium complex. After crossing a four-membered-ring transition state, ethylene inserts into the Li-C bond. The insertion barriers for the eight reactions are in the range of 6.9-11.0 kcal/mol, comparable to those of ethylene cationic coordination polymerizations. However, the polymerization activities of ethylene anionic polymerizations are much lower than those of cationic coordination polymerizations. Comparing the energy profiles of these ethylene anionic polymerizations with those of cationic coordination polymerizations, it can be found that the transition states in the ethylene anionic polymerizations are higher in energy than the reactants, while the transition states in ethylene cationic coordination polymerizations are lower than the reactants. Therefore, ethylene anionic polymerizations need additional energy to climb the energy barriers, while the energies for overcoming the transition states in the cationic coordination polymerizations can be obtained from reactants that are higher in energy than the reactants. We reason the differences in their energy profiles could be one of the reasons for the lower activity of ethylene anionic polymerization than ethylene cationic coordination polymerization despite their comparable insertion barriers.


Assuntos
Simulação por Computador , Diaminas/química , Etilenos/síntese química , Modelos Químicos , Compostos Organometálicos/química , Etilenos/química , Estrutura Molecular , Teoria Quântica
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