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https://www.readbyqxmd.com/read/28218849/theoretical-study-of-the-heterolytic-%C3%AF-bond-cleavage-on-the-ge%C3%A2-o-bond-of-germanone-an-insight-into-the-driving-force-from-both-electronic-and-dynamical-aspects
#1
Toshiaki Matsubara, Tomoyoshi Ito
The mechanism of the σ bond cleavage of H2O, NH3, Me2C═O, H2, CH4, BH3, and SiH4 on the Ge═O bond of germanone is examined by means of both quantum mechanical (QM) and molecular dynamics (MD) methods. The QM calculations show that the σ bonds of all the substrates are heterolytically broken on the very largely polarized Ge═O bond. Before the σ bond cleavage, the substrate at first approach the Ge═O germanium in the cases of H2O, Me2C═O, and NH3, and in contrast, the Ge═O oxygen in the cases of H2, CH4, BH3, and SiH4...
February 20, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28215535/ambra1-a-novel-bh3-like-protein-new-insights-into-the-ambra1-bcl2-family-proteins-relationship
#2
A Di Rita, F Strappazzon
Cellular homeostasis swings like a pendulum backward and forward between life and death. Two of the main processes, which regulate this equilibrium, are autophagy and apoptosis. While autophagy is a highly conserved self-digestion mechanism that mediates degradation of damaged or surplus components, apoptosis is a programmed cell suicide in which typical death signals induce the elimination of undesired cells. Both these processes are highly regulated by complex molecular machineries, including some common proteins whose "dual role" favors one process or the other...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28209992/from-basic-apoptosis-discoveries-to-advanced-selective-bcl-2-family-inhibitors
#3
REVIEW
Avi Ashkenazi, Wayne J Fairbrother, Joel D Leverson, Andrew J Souers
Members of the B cell lymphoma 2 (BCL-2) gene family have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event; accordingly, selective inhibition of specific anti-apoptotic BCL-2 family proteins represents an exciting therapeutic opportunity. A combination of nuclear magnetic resonance (NMR)-based screening and structure-based drug design has yielded the first bona fide BCL-2 homology 3 (BH3) mimetics, including the BCL-2 and BCL-XL dual antagonist navitoclax, which is the first BCL-2 family inhibitor to show efficacy in patients with cancer...
February 17, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28202514/mcl-1-degradation-is-required-for-targeted-therapeutics-to-eradicate-colon-cancer-cells
#4
Jingshan Tong, Peng Wang, Shuai Tan, Dongshi Chen, Zaneta Nikolovska-Coleska, Fangdong Zou, Jian Yu, Lin Zhang
The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28197319/structure-based-design-of-non-natural-peptidic-macrocyclic-mcl-1-inhibitors
#5
Jeffrey W Johannes, Stephanie Bates, Carl Beigie, Matthew A Belmonte, John Breen, Shenggen Cao, Paolo A Centrella, Matthew A Clark, John W Cuozzo, Christoph E Dumelin, Andrew D Ferguson, Sevan Habeshian, David Hargreaves, Camil Joubran, Steven Kazmirski, Anthony D Keefe, Michelle L Lamb, Haiye Lan, Yunxia Li, Hao Ma, Scott Mlynarski, Martin J Packer, Philip B Rawlins, Daniel W Robbins, Haidong Shen, Eric A Sigel, Holly H Soutter, Nancy Su, Dawn M Troast, Haiyun Wang, Kate F Wickson, Chengyan Wu, Ying Zhang, Qiuying Zhao, Xiaolan Zheng, Alexander W Hird
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28187446/targeting-of-apoptotic-pathways-by-smac-or-bh3-mimetics-distinctly-sensitizes-paclitaxel-resistant-triple-negative-breast-cancer-cells
#6
Effrosini G Panayotopoulou, Anna-Katharina Müller, Melanie Börries, Hauke Busch, Guohong Hu, Sima Lev
Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines...
February 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28182867/disordered-clusters-of-bak-dimers-rupture-mitochondria-during-apoptosis
#7
Rachel T Uren, Martin O'Hely, Sweta Iyer, Ray Bartolo, Melissa X Shi, Jason M Brouwer, Amber E Alsop, Grant Dewson, Ruth M Kluck
During apoptosis, Bak and Bax undergo major conformational change and form symmetric dimers that coalesce to perforate the mitochondrial outer membrane via an unknown mechanism. We have employed cysteine labelling and linkage analysis to the full length of Bak in mitochondria. This comprehensive survey showed that in each Bak dimer the N-termini are fully solvent-exposed and mobile, the core is highly structured, and the C-termini are flexible but restrained by their contact with the membrane. Dimer-dimer interactions were more labile than the BH3:groove interaction within dimers, suggesting there is no extensive protein interface between dimers...
February 6, 2017: ELife
https://www.readbyqxmd.com/read/28182770/biochemical-and-biophysical-investigations-of-the-interaction-between-human-glucokinase-and-pro-apoptotic-bad
#8
Alix Rexford, Diego A R Zorio, Brian G Miller
The glycolytic enzyme glucokinase (GCK) and the pro-apoptotic protein BAD reportedly reside within a five-membered complex that localizes to the mitochondria of mammalian hepatocytes and pancreatic β-cells. Photochemical crosslinking studies using a synthetic analog of BAD's BH3 domain and in vitro transcription/translation experiments support a direct interaction between BAD and GCK. To investigate the biochemical and biophysical consequences of the BAD:GCK interaction, we developed a method for the production of recombinant human BAD...
2017: PloS One
https://www.readbyqxmd.com/read/28182005/constitutive-p53-heightens-mitochondrial-apoptotic-priming-and-favors-cell-death-induction-by-bh3-mimetic-inhibitors-of-bcl-xl
#9
J Le Pen, L Maillet, K Sarosiek, C Vuillier, F Gautier, S Montessuit, J C Martinou, A Letaï, F Braun, P P Juin
No abstract text is available yet for this article.
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28170214/determinants-of-bh3-sequence-specificity-for-the-disruption-of-bcl-xl-cbid-complexes-in-membranes
#10
Kushal Kumar Das, Raed Shalaby, Ana J García-Sáez
The prosurvival Bcl-2 proteins exhibit a specific pattern of interactions with BH3-only proteins that determines the cellular dependence to apoptotic stress. This specificity is crucial for the development of BH3 mimetics, a class of anti-cancer molecules based on the BH3 domain with promising activity in clinical trials. Although complex formation mainly takes place in the mitochondrial outer membrane, most studies so far addressed the interaction between BH3 peptides and truncated Bcl-2 proteins in solution...
February 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28167500/mirnas-cooperate-in-apoptosis-regulation-during-c-elegans-development
#11
Ryan Sherrard, Sebastian Luehr, Heinke Holzkamp, Katherine McJunkin, Nadin Memar, Barbara Conradt
Programmed cell death occurs in a highly reproducible manner during Caenorhabditis elegans development. We demonstrate that, during embryogenesis, miR-35 and miR-58 bantam family microRNAs (miRNAs) cooperate to prevent the precocious death of mothers of cells programmed to die by repressing the gene egl-1, which encodes a proapoptotic BH3-only protein. In addition, we present evidence that repression of egl-1 is dependent on binding sites for miR-35 and miR-58 family miRNAs within the egl-1 3' untranslated region (UTR), which affect both mRNA copy number and translation...
February 6, 2017: Genes & Development
https://www.readbyqxmd.com/read/28161988/therapeutic-inhibition-of-bcl-2-and-related-family-members
#12
Michelle Levy, David Claxton
BCL-2 proteins are key players in the balance of cell life and death. Their roles in the development and biology of cancer have been well established and continue to be investigated. Understanding the mechanisms by which these proteins regulate apoptosis has led to the development of small molecule targeted therapies that act to overcome the cell's ability to evade programmed cell death. Areas covered: The biology of the intrinsic apoptotic pathway is reviewed with attention to the varied roles of the anti-apoptotic members of the BCL-2 family...
February 6, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28140720/pathways-and-mechanisms-of-venetoclax-resistance
#13
Prithviraj Bose, Varsha Gandhi, Marina Konopleva
The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax...
January 31, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28138035/co-targeting-hgf-cmet-signaling-with-mek-inhibitors-in-metastatic-uveal-melanoma
#14
Hanyin Cheng, Vivian Chua, Connie Liao, Timothy J Purwin, Mizue Terai, Ken Kageyama, Michael A Davies, Takami Sato, Andrew E Aplin
Metastatic uveal melanoma (UM) patients usually die within one year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in UM patients. Our previous work showed that HGF signaling elicits resistance to MEK inhibitors in metastatic UM. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and BMF, contributes to HGF-mediated resistance to MEK inhibitors...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28134252/thz1-targeting-cdk7-suppresses-stat-transcriptional-activity-and-sensitizes-t-cell-lymphomas-to-bcl2-inhibitors
#15
Florencia Cayrol, Pannee Praditsuktavorn, Tharu M Fernando, Nicholas Kwiatkowski, Rosella Marullo, M Nieves Calvo-Vidal, Jude Phillip, Benet Pera, Shao Ning Yang, Kaipol Takpradit, Lidia Roman, Marcello Gaudiano, Ramona Crescenzo, Jia Ruan, Giorgio Inghirami, Tinghu Zhang, Graciela Cremaschi, Nathanael S Gray, Leandro Cerchietti
Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R...
January 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28125090/loss-of-gcn5-leads-to-increased-neuronal-apoptosis-by-upregulating-e2f1-and-egr-1-dependent-bh3-only-protein-bim
#16
Yanna Wu, Shanshan Ma, Yong Xia, Yangpeng Lu, Shiyin Xiao, Yali Cao, Sidian Zhuang, Xiangpeng Tan, Qiang Fu, Longchang Xie, Zhiming Li, Zhongmin Yuan
Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons...
January 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28120212/ym155-enhances-abt-737-mediated-apoptosis-through-mcl-1-downregulation-in-mcl-1-overexpressed-cancer-cells
#17
Seon Min Woo, Kyoung-Jin Min, Bo Ram Seo, Young Ho Seo, Yong-Jin Jeong, Taeg Kyu Kwon
ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2, and Bcl-w, and it has been reported for anti-cancer effects in various types of cancer cells. However, ABT-737 fails to induce apoptosis in cancer cell with high levels of Mcl-1 expression. The pharmacological survivin inhibitor YM155 has been reported to induce downregulation of Mcl-1 expression. Therefore, we investigated the effect of YM155 to sensitize resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. We found that ABT-737 alone and YM155 alone did not induce apoptosis, but YM155 markedly sensitized ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma cells (U251MG), and human lung carcinoma cells (A549)...
January 24, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28119805/how-to-unleash-mitochondrial-apoptotic-blockades-to-kill-cancers
#18
REVIEW
Jing Deng
Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades...
January 2017: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/28111464/bruton-s-tyrosine-kinase-inhibition-increases-bcl-2-dependence-and-enhances-sensitivity-to-venetoclax-in-chronic-lymphocytic-leukemia
#19
J Deng, E Isik, S M Fernandes, J R Brown, A Letai, M S Davids
Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (CLL), it does not induce substantial apoptosis in vitro, and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib...
February 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28106939/maximizing-output-in-rna-programmed-peptidyl-transfer-reactions
#20
Margherita Di Pisa, Anett Hauser, Oliver Seitz
A chemical reaction that is triggered by specific RNA molecules may provide opportunities for the design of artificial feedback loops. We envision a peptidyl transfer reaction, in which mRNA encoding for antiapoptotic protein would instruct the synthesis of apoptosis-inducing peptides. In this study, we tackled the RNA-programmed synthesis of a 16mer peptide derived from the Bak-BH3 protein which inhibits the antiapoptotic protein Bcl-xL. The reaction involves the transfer of a thioester-linked donor peptide fragment from one PNA conjugate onto an acceptor peptide-PNA conjugate...
January 20, 2017: Chembiochem: a European Journal of Chemical Biology
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