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金雀异黄素调控Egr1/PTEN信号通路诱导卵巢癌SKOV3细胞凋亡的实验研究
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盛连兵,孙凯,刘海萍,郝天羽,武斌
- , 2017,
Abstract: 目的?通过金雀异黄素(genistein)诱导人卵巢癌细胞SKOV3细胞的凋亡,探讨即刻早期反应基因(Egr1)/细胞骨架蛋白同源在10号染色体有缺失的磷酸酶(PTEN)信号通路在金雀异黄素诱导SKOV3细胞凋亡过程中的作用。方法?应用磺酰罗丹明B(SRB)染色法测定经金雀异黄素处理后的SKOV3卵巢癌细胞生长抑制率,组蛋白DNA酶联免疫吸附测定(ELISA)法检测细胞凋亡,采用游离硝基苯胺(pNA)法检测细胞内半胱氨酸天冬氨酸特异性蛋白酶3(Caspase-3)的蛋白含量,实时荧光定量PCR(Real- time PCR)测定细胞内Bcl-2相关X蛋白基因(bax)和B淋巴细胞瘤-2基因(bcl-2)的基因表达变化,蛋白质印迹法(Western blotting)分析Egr1、PTEN、蛋白激酶B(AKT)、磷酸化蛋白激酶B(p-Akt)蛋白的表达变化。结果?金雀异黄素显著抑制卵巢癌细胞SKOV3的增殖(P<0.05),并呈浓度依赖性。金雀异黄素处理24 h后,处理浓度高于40 μmol/L时,与对照组相比,调亡指数、Caspase-3活性、bax的相对表达及细胞中Egr1蛋白和PTEN蛋白的表达量均显著增加(P<0.05),Bcl-2的相对表达量及AKT蛋白的磷酸化水平p-Akt则显著降低(P<0.05)。当同时给予50 nmol/L PTEN抑制剂Bpv后,p-Akt表达明显增加,细胞凋亡程度受到明显抑制。结论?金雀异黄素可能通过上调Egr1/PTEN信号通路的表达抑制PI3K/Akt信号通路的激活诱导SKOV3细胞凋亡,进一步影响了调亡相关基因Bcl-2、Bax及Caspase-3的表达。
Paclitaxel-Induced Apoptosis Is BAK-Dependent, but BAX and BIM-Independent in Breast Tumor  [PDF]
Anna V. Miller, Mark A. Hicks, Wataru Nakajima, Amanda C. Richardson, Jolene J. Windle, Hisashi Harada
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060685
Abstract: Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim?/? MEFs (mouse embryonic fibroblasts), the bim?/? mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak?/? MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax?/? MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.
Regulation of the Tumor Suppressor PTEN through Exosomes: A Diagnostic Potential for Prostate Cancer  [PDF]
Kathleen Gabriel, Alistair Ingram, Richard Austin, Anil Kapoor, Damu Tang, Fadwa Majeed, Talha Qureshi, Khalid Al-Nedawi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070047
Abstract: PTEN is a potent tumor-suppressor protein. Aggressive and metastatic prostate cancer (PC) is associated with a reduction or loss of PTEN expression. PTEN reduction often occurs without gene mutations, and its downregulation is not fully understood. Herein, we show that PTEN is incorporated in the cargo of exosomes derived from cancer cells. PTEN is not detected in exosomes derived from normal, noncancerous cells. We found that PTEN can be transferred to other cells through exosomes. In cells that have a reduction or complete loss of PTEN expression, the transferred PTEN is competent to confer tumor-suppression activity to acceptor cells. In PC patients, we show that PTEN is incorporated in the cargo of exosomes that circulate in their blood. Interestingly, normal subjects have no PTEN expression in their blood exosomes. Further, we found that the prostate-specific antigen (PSA) is incorporated in PC patients’ and normal subjects’ blood exosomes. These data suggest that exosomal PTEN can compensate for PTEN loss in PTEN deficient cells, and may have diagnostic value for prostate cancer.
BIM in Multifamily Design & Construction  [PDF]
Matt Jefferies, Swarnali Ghosh Dastider
Journal of Building Construction and Planning Research (JBCPR) , 2018, DOI: 10.4236/jbcpr.2018.64022
Abstract: In 2014, the National Association of Homebuilders conducted an initial survey about the use of Building Information Modeling (BIM) in residential construction. They found that BIM had not been widely adopted, but there was interest in future use. Four years later, the authors, Prof. Ghosh Dastider and Matt Jefferies at Washington University in St. Louis used a similar methodology to see what has changed. They found a significant increase in BIM’s application in the multifamily residential industry. Based on data collected from the re-conducted survey, the authors concluded with the future predictions on how use of BIM will accelerate in residential construction market in next few years. Few significant findings indicate increased use of BIM among contractors along with design built firms, as well as during the construction phase and life cycle analysis.
CHIP Regulates AKT/FoxO/Bim Signaling in MCF7 and MCF10A Cells  [PDF]
Yanrong Lv, Shanshan Song, Kai Zhang, Haidong Gao, Rong Ma
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083312
Abstract: A number of studies have shown that apoptosis resistance can be observed in multiple human tumors; however the detailed mechanism remains unclear. In the present study, we demonstrated that the abnormal overexpression of the C terminus of Hsc70-interacting protein (CHIP) induced apoptosis resistance by regulating the AKT/FoxO/Bim signaling pathway in the breast cancer cell MCF7 and the human non-tumorigenic cell MCF10A. We found that CHIP overexpression in MCF7 and MCF10A cells activated AKT and inhibited the Forkhead box O (FoxO) transcription factors FoxO1, FoxO3, and FoxO4, thereby inhibiting transcription of the target genes bim and pten. Inhibition of PI3K by a chemical reagent revealed that these events may be critical for CHIP-induced apoptosis resistance. We also determined that inhibition of FoxO3 by CHIP led to the decrease in PTEN and further activated the AKT survival pathway. We corroborated our findings in breast cancer tissues. In general, the CHIP-modulated AKT/FoxO/Bim signaling pathway was shown to induce apoptosis resistance by decreasing the protein level of the tumor suppressor PTEN in both transcriptional and post-translational regulations.
Identification of cis-Acting Elements and Splicing Factors Involved in the Regulation of BIM Pre-mRNA Splicing  [PDF]
Wen Chun Juan, Xavier Roca, S. Tiong Ong
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095210
Abstract: Aberrant changes in the expression of the pro-apoptotic protein, BCL-2-like 11 (BIM), can result in either impaired or excessive apoptosis, which can contribute to tumorigenesis and degenerative disorders, respectively. Altering BIM pre-mRNA splicing is an attractive approach to modulate apoptosis because BIM activity is partly determined by the alternative splicing of exons 3 or 4, whereby exon 3-containing transcripts are not apoptotic. Here we identified several cis-acting elements and splicing factors involved in BIM alternative splicing, as a step to better understand the regulation of BIM expression. We analyzed a recently discovered 2,903-bp deletion polymorphism within BIM intron 2 that biased splicing towards exon 3, and which also impaired BIM-dependent apoptosis. We found that this region harbors multiple redundant cis-acting elements that repress exon 3 inclusion. Furthermore, we have isolated a 23-nt intronic splicing silencer at the 3′ end of the deletion that is important for excluding exon 3. We also show that PTBP1 and hnRNP C repress exon 3 inclusion, and that downregulation of PTBP1 inhibited BIM-mediated apoptosis. Collectively, these findings start building our understanding of the cis-acting elements and splicing factors that regulate BIM alternative splicing, and also suggest potential approaches to alter BIM splicing for therapeutic purposes.
Building Information Model (BIM)  [PDF]
Ye.V. Krinitskiy
Magazine of Civil Engineering , 2010,
Abstract: One of the most interesting topics in the field of automated design is a concept known as the "building information model." Since the beginning of the computer-aided design application it became possible to draw in three dimensional space, using real models of objects that contain the complete technical information, which is necessary for the whole system calculation and the unique identification of objects. This allows us to solve problems related to control the changes in the drawings.But during the life cycle of a building information can be changed, supplemented, and to unite. To realize this idea it is necessary to create unified standard for storing and sharing such information, which is independent from specific software and contains all the necessary and sufficient information to ensure the building's life cycle. The aim of BIM is the creation of a unified base for the such standard.In this paper details the functions and tasks of BIM, and shows the existing alternative standards, which realize the BIM at the moment.
SHAVING BIM: ESTABLISHING A FRAMEWORK FOR FUTURE BIM RESEARCH IN NEW ZEALAND  [PDF]
Tran, Van,Tookey, John E.,Roberti, Johannes
International Journal of Construction Supply Chain Management , 2012,
Abstract: This paper reviews and analyses issues relating to the uptake of BIM in the NZ construction industry. There have been few BIM applications in NZ; in particular, in post-construction phases like facilities management, there is none. The paper found that the three reasons why BIM has not been widely accepted and used in New Zealand are: the slow uptake by NZ construction companies; a lack of Kiwi-focused BIM initiatives (led by the government and industry bodies); and a lack of BIM-based building life cycle considerations. Therefore, the paper concludes that there is an urgent need for a joint research programme in NZ to develop a Kiwi-oriented knowledge base on BIM. Given the fact that all major research organisations currently have development plans in their pipelines, coupled with potential developments of the Christchurch Cit after the quake, it seems an ideal time to take a BIM-based research initiative in the country. This joint BIM- focused research programme should concentrate on construction management processes, including procurement management, contract management, information management, as well as post-construction aspects such as facility management.
Combined Phosphatase and Tensin Homolog (PTEN) Loss and Fatty Acid Synthase (FAS) Overexpression Worsens the Prognosis of Chinese Patients with Hepatocellular Carcinoma  [PDF]
Xuehua Zhu,Xia Qin,Maogui Fei,Wenmin Hou,Joel Greshock,Kurtis E. Bachman,Richard Wooster,Jiuhong Kang,Crystal Ying Qin
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms13089980
Abstract: We aimed to investigate the expression pattern of phosphatase and tensin homolog (PTEN), to evaluate the relationship between PTEN expression and clinicopathological characteristics, including fatty acid synthase (FAS) expression, and to determine the correlations of PTEN and FAS expression with survival in Chinese patients with hepatocellular carcinoma (HCC). The expression patterns of PTEN and FAS were determined using tissue microarrays and immunohistochemistry. The expression of PTEN was compared with the clinicopathological characteristics of HCC, including FAS expression. Receiver operator characteristic curves were used to calculate the clinical sensitivity and specificity of PTEN expression. Kaplan-Meier survival curves were constructed to evaluate the correlations of PTEN loss and FAS overexpression with overall survival. We found that the loss of PTEN expression occurred predominantly in the cytoplasm, while FAS was mainly localized to the cytoplasm. Cytoplasmic and total PTEN expression levels were significantly decreased in HCC compared with adjacent non-neoplastic tissue (both, p < 0.0001). Decreased cytoplasmic and total PTEN expression showed significant clinical sensitivity and specificity for HCC (both, p < 0.0001). Downregulation of PTEN in HCC relative to non-neoplastic tissue was significantly correlated with histological grade ( p = 0.043 for histological grades I–II versus grade III). Loss of total PTEN was significantly correlated with FAS overexpression ( p = 0.014). Loss of PTEN was also associated with poor prognosis of patients with poorly differentiated HCC ( p = 0.049). Moreover, loss of PTEN combined with FAS overexpression was associated with significantly worse prognosis compared with other HCC cases ( p = 0.011). Our data indicate that PTEN may serve as a potential diagnostic and prognostic marker of HCC. Upregulating PTEN expression and inhibiting FAS expression may offer a novel therapeutic approach for HCC.
The Role of PTEN in Tumor Angiogenesis
Stéphane Rodriguez,Uyen Huynh-Do
Journal of Oncology , 2012, DOI: 10.1155/2012/141236
Abstract: During the past 20 years, the phosphatase and tensin homolog PTEN has been shown to be involved in major physiological processes, and its mutation or loss is often associated with tumor formation. In addition PTEN regulates angiogenesis not only through its antagonizing effect on the PI3 kinase pathway mainly, but also through some phosphatase-independent functions. In this paper we delineate the role of this powerful tumor suppressor in tumor angiogenesis and dissect the underlying molecular mechanisms. Furthermore, it appears that, in a number of cancers, the PTEN status determines the response to chemotherapy, highlighting the need to monitor PTEN expression and to develop PTEN-targeted therapies.
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