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bcl-2 interacting killer

Jie Liu, Guang-Hui Wang, Ying-Hui Duan, Yi Dai, Yuzhou Bao, Mengjie Hu, Yu-Qi Zhou, Mingyu Li, Fuquan Jiang, Hu Zhou, Xin-Sheng Yao, Xiao-Kun Zhang
Orphan nuclear receptor Nur77 promotes apoptosis by targeting mitochondria through interaction with Bcl-2, an event that converts Bcl-2 from a survival to killer. However, how the Nur77-Bcl-2 apoptotic pathway is regulated remains largely unknown. In this study, we examined the regulation of the Nur77-Bcl-2 pathway by CCE9, a xanthone compound. Our results demonstrated that the apoptotic effect of CCE9 depended on its induction of Nur77 expression, cytoplasmic localization, and mitochondrial targeting. The activation of the Nur77-Bcl-2 pathway by CCE9 was associated with its activation of p38α MAPK...
July 13, 2017: Oncotarget
Yinan Wang, Yao Liu, Chunfang Hu, Xiaoyan Ni, Xiaobo Huang
Although the newly identified protein tumor necrosis factor α-induced protein 8-like 1 (TNFAIP8L1), also known as TIPE1, has been reported to be able to induce apoptosis in human hepatocellular carcinoma cells, the involvement of TIPE1 in apoptosis remains to be elucidated. The present study investigated the pro-apoptotic effect of TIPE1 in an murine macrophage cell line, RAW264.7. The cell apoptosis rate was detected by flow cytometry. The results revealed that overexpressed TIPE1 could directly enhance the apoptosis and the cisplatin-induced cell death of RAW264...
November 2016: Oncology Letters
Mark P A Luna-Vargas, Jerry Edward Chipuk
Cellular commitment to the mitochondrial pathway of apoptosis is accomplished when proapoptotic B cell chronic lymphocytic leukemia/lymphoma (BCL)-2 proteins compromise mitochondrial integrity through the process of mitochondrial outer membrane permeabilization (MOMP). For nearly three decades, intensive efforts focused on the identification and interactions of two key proapoptotic BCL-2 proteins: BCL-2 antagonist killer (BAK) and BCL-2-associated X (BAX). Indeed, we now have critical insights into which BCL-2 proteins interact with BAK/BAX to either preserve survival or initiate MOMP...
December 2016: Trends in Cell Biology
Shi Zhong, You-Gui Li, Dong-Feng Ji, Tian-Bao Lin, Zhi-Qiang Lv
Protocatechualdehyde (PCA) extracted from Phellinus gilvus exhibits anti-cancer activity in human colorectal carcinoma cells (HT-29). However, the underlying mechanisms remain poorly understood. We performed an in vitro study involving MTT, flow cytometry, RT-PCR, and western blot analyses to investigate the effects of PCA treatment on cell proliferation, cell cycle distribution, apoptosis, and expression of several cell cycle-related genes in HT-29 cells. The treatment enhanced S-phase cell cycle and apoptosis in HT-29 cells in a dose-dependent manner...
July 19, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Matthew J Carter, Mark S Cragg
The B-cell receptor (BCR) represents a key driver of B-cell development. Consequently, multiple mechanisms link inappropriate BCR signaling to apoptosis. Recently, we characterized the molecular regulators involved in lymphoma cells, confirming a major role for Bcl-2 interacting mediator of cell death (Bim) and supplementary roles for Bcl-2 interacting killer (Bik) and Noxa, and showing that all 3 proteins are required for maximal apoptosis.
March 2016: Molecular & Cellular Oncology
Susan Lee, Thomas E Wales, Silvia Escudero, Daniel T Cohen, James Luccarelli, Catherine G Gallagher, Nicole A Cohen, Annissa J Huhn, Gregory H Bird, John R Engen, Loren D Walensky
MCL-1 is an antiapoptotic BCL-2 family protein that has emerged as a major pathogenic factor in human cancer. Like BCL-2, MCL-1 bears a surface groove whose function is to sequester the BH3 killer domains of proapoptotic BCL-2 family members, a mechanism harnessed by cancer cells to establish formidable apoptotic blockades. Although drugging the BH3-binding groove has been achieved for BCL-2, translating this approach to MCL-1 has been challenging. Here, we report an alternative mechanism for MCL-1 inhibition by small-molecule covalent modification of C286 at a new interaction site distant from the BH3-binding groove...
June 2016: Nature Structural & Molecular Biology
Vrajesh Pandya, Darryl Glubrecht, Larissa Vos, John Hanson, Sambasivarao Damaraju, John Mackey, Judith Hugh, Ing Swie Goping
Breast cancer is the leading cause of cancer-associated deaths in women worldwide. Clinical biomarkers give information on disease progression and identify relevant biological pathways. A confounding factor that uncouples markers from disease outcome is the ability of tumor cells to mutate and evade clinical intervention. Therefore, we focussed on apoptotic genes that modulate tumor regression. Using gene and tissue microarray analyses, we identified an association of Bcl-2 interacting killer (Bik) with poor breast cancer prognosis...
May 31, 2016: Oncotarget
Wei Yuan, Zhou Zhang, Binghua Dai, Qing Wei, Jinjin Liu, Yuzhen Liu, Yun Liu, Lin He, Daizhan Zhou
BACKGROUND: Genomic alterations of small bowel cancers remain poorly understood due to the rarity of these diseases. In the current study, the authors report the identification of somatic mutations from patients with duodenal adenocarcinoma by whole-exome sequencing. METHODS: Whole-exome sequencing and follow-up analysis were conducted in 12 matched tumor-normal tissue duodenal adenocarcinoma tissue pairs to examine the genetic characteristics of this disease. Somatic mutations (single-nucleotide variants and short insertion/deletions) were obtained and filtered and then searched for recurrently mutated genes and pathways...
June 1, 2016: Cancer
Anna Ridley, Hiroko Hatano, Isabel Wong-Baeza, Jacqueline Shaw, Katherine K Matthews, Hussein Al-Mossawi, Kristin Ladell, David A Price, Paul Bowness, Simon Kollnberger
OBJECTIVE: In the spondyloarthritides (SpA), increased numbers of CD4+ T cells express killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2). The aim of this study was to determine the factors that induce KIR-3DL2 expression, and to characterize the relationship between HLA-B27 and the phenotype and function of KIR-3DL2-expressing CD4+ T cells in SpA. METHODS: In total, 34 B27+ patients with SpA, 28 age- and sex-matched healthy controls (20 B27- and 8 B27+), and 9 patients with rheumatoid arthritis were studied...
April 2016: Arthritis & Rheumatology
Ren-Ping Zheng, Wei Wang, Chuan-Dong Wei
Despite the improvement in chemotherapeutic agents, the outcome of patients with prostate cancer remains poor. It is therefore imperative that new anticancer drugs are explored. The aim of the present study was to investigate the inhibitory effect of bortezomib on DU145 prostate cancer cells. The DU145 cell proliferation rate was detected via MTT assay prior to and following exposure to various concentrations of bortezomib, and the level of cell apoptosis and the cell cycle distribution were tested using flow cytometry...
September 2015: Experimental and Therapeutic Medicine
D Senft, A Weber, F Saathoff, C Berking, M V Heppt, C Kammerbauer, S Rothenfusser, S Kellner, Z Kurgyis, R Besch, G Häcker
Mitochondrial apoptosis is controlled by proteins of the B-cell lymphoma 2 (Bcl-2) family. Pro-apoptotic members of this family, known as BH3-only proteins, initiate activation of the effectors Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), which is counteracted by anti-apoptotic family members. How the interactions of Bcl-2 proteins regulate cell death is still not entirely clear. Here, we show that in the absence of extrinsic apoptotic stimuli Bak activates without detectable contribution from BH3-only proteins, and cell survival depends on anti-apoptotic Bcl-2 molecules...
2015: Cell Death & Disease
Kimberly E Maxfield, Patrick J Taus, Kathleen Corcoran, Joshua Wooten, Jennifer Macion, Yunyun Zhou, Mark Borromeo, Rahul K Kollipara, Jingsheng Yan, Yang Xie, Xian-Jin Xie, Angelique W Whitehurst
Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer-testis antigens (CTAs). The extent to which CTA expression represents epiphenomena or confers tumorigenic traits is unknown. In this study, to address this, we implemented a multidimensional functional genomics approach that incorporates 7 different phenotypic assays in 11 distinct disease settings. We identify 26 CTAs that are essential for tumor cell viability and/or are pathological drivers of HIF, WNT or TGFβ signalling...
November 16, 2015: Nature Communications
Dámaso Sánchez-Carrera, Mikel García-Puga, Lucrecia Yáñez, Íñigo Romón, Carlos Pipaón
Inactivation of p53 is one of the most relevant events in human cancer, since it allows transformed cells to escape their own proliferation control and leave them irresponsive to drugs that aim to damage their DNA. When p53 falls, other members of its family may become targets to attack tumoural cells. p73 has shown capacity to mediate these attacks. However, its N-terminal truncated isoforms have been associated with oncogenesis due to their capacity to act as dominant negatives of p53 and the transactivation (TA) isoforms of p73...
April 28, 2015: Bioscience Reports
Ece Konac, Nuray Varol, Ilker Kiliccioglu, Cenk Y Bilen
The proteasome inhibitor bortezomib is a promising novel agent in bladder cancer therapy; however, inducible cytoprotective mechanisms may limit its potential efficacy. To date, the cellular and molecular effects of proteasome inhibitors on bladder cancer cells have been poorly characterized. Despite the consistent rate of initial responses, cisplatin treatment typically results in the development of chemoresistance, leading to therapeutic failure. Therefore, the present study aimed to characterize the molecular mechanisms underlying the anti-proliferative effects of cisplatin and bortezomib combination therapy on the human T24 bladder cancer cell line, by analyzing the protein expression levels of apoptotic genes...
July 2015: Oncology Letters
Xiang-Dong Han, Zhi-Wei Zhou, Wei Yang, Hang-Cheng Ye, Ying-Zi Xu, Yun-Feng Huang, Tong Zhang, Shu-Feng Zhou
Ischemic heart disease (IHD) is the leading cause of death worldwide and remains a major life-threatening factor in humans. Apoptosis has been implicated in the pathogenesis of IHD. The Chinese herbal formula Huo Luo Xiao Ling Dan (HLXLD), one of the commonly used Chinese herbal formulas, consists of Salviae miltiorrhizae, Angelica sinensis, Gummi olibanum, and Commiphora myrrha, with a wide spectrum of pharmacological activity. However, the mechanism of action and molecular targets of HLXLD in the treatment of IHD are unclear...
2015: Drug Design, Development and Therapy
Erinna F Lee, Grant Dewson, Marco Evangelista, Anne Pettikiriarachchi, Grace J Gold, Haoran Zhu, Peter M Colman, W Douglas Fairlie
Bcl-2 homology 3 (BH3) domains are short sequence motifs that mediate nearly all protein-protein interactions between B cell lymphoma 2 (Bcl-2) family proteins in the intrinsic apoptotic cell death pathway. These sequences are found on both pro-survival and pro-apoptotic members, although their primary function is believed to be associated with induction of cell death. Here, we identify critical features of the BH3 domains of pro-survival proteins that distinguish them functionally from their pro-apoptotic counterparts...
December 26, 2014: Journal of Biological Chemistry
Peter K Lauf, Tariq Alqahtani, Karin Flues, Jaroslaw Meller, Norma C Adragna
In silico analysis predicts interaction between Na-K-ATPase (NKA) and Bcl-2 protein canonical BH3- and BH1-like motifs, consistent with NKA inhibition by the benzo-phenanthridine alkaloid chelerythrine, a BH3 mimetic, in fetal human lens epithelial cells (FHLCs) (Lauf PK, Heiny J, Meller J, Lepera MA, Koikov L, Alter GM, Brown TL, Adragna NC. Cell Physiol Biochem 31: 257-276, 2013). This report establishes proof of concept: coimmunoprecipitation and immunocolocalization showed unequivocal and direct physical interaction between NKA and Bcl-2 proteins...
January 1, 2015: American Journal of Physiology. Cell Physiology
Lu Luo, Jun Yang, Dongxiang Liu
Bax is a pro-apoptotic Bcl-2 family protein. The activated Bax translocates to mitochondria, where it forms pore and permeabilizes the mitochondrial outer membrane. This process requires the BH3-only activator protein (i.e. tBid) and can be inhibited by anti-apoptotic Bcl-2 family proteins such as Bcl-xL. Here by using single molecule fluorescence techniques, we studied the integration and oligomerization of Bax in lipid bilayers. Our study revealed that Bax can bind to lipid membrane spontaneously in the absence of tBid...
November 14, 2014: Journal of Biological Chemistry
Xian Jiang, Hui Jiang, Zhirong Shen, Xiaodong Wang
Intrinsic apoptotic stimuli initiate mammalian cells' apoptotic program by first activating the proteins that have only Bcl-2 homology domain 3 (BH3), such as Bcl-2 interacting mediator of cell death (Bim) and truncated BH3 interacting death domain agonist (tBid), which in turn trigger conformational changes in BCL2-associated X (Bax) and BCL2-antagonist/killer (Bak) proteins that enable oligomer formation on the mitochondria, causing cytochrome c and other apoptogenic proteins in the intermembrane space to leak out...
October 14, 2014: Proceedings of the National Academy of Sciences of the United States of America
Amy M Sainski, Haiming Dai, Sekar Natesampillai, Yuan-Ping Pang, Gary D Bren, Nathan W Cummins, Cristina Correia, X Wei Meng, James E Tarara, Marina Ramirez-Alvarado, David J Katzmann, Christina Ochsenbauer, John C Kappes, Scott H Kaufmann, Andrew D Badley
Previous studies have shown that human immunodeficiency virus (HIV) protease cleaves procaspase 8 to a fragment, termed Casp8p41, that lacks caspase activity but nonetheless contributes to T cell apoptosis. Herein, we show that Casp8p41 contains a domain that interacts with the BH3-binding groove of pro-apoptotic Bak to cause Bak oligomerization, Bak-mediated membrane permeabilization, and cell death. Levels of active Bak are higher in HIV-infected T cells that express Casp8p41. Conversely, targeted mutations in the Bak-interacting domain diminish Bak binding and Casp8p41-mediated cell death...
September 29, 2014: Journal of Cell Biology
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