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Bcl-2 family proteins

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https://www.readbyqxmd.com/read/28079890/structural-insight-into-an-evolutionarily-ancient-programmed-cell-death-regulator-the-crystal-structure-of-marine-sponge-bhp2-bound-to-lb-bak-2
#1
Sofia Caria, Mark G Hinds, Marc Kvansakul
Sponges of the porifera family harbor some of the evolutionary most ancient orthologs of the B-cell lymphoma-2 (Bcl-2) family, a protein family critical to regulation of apoptosis. The genome of the sponge Geodia cydonium contains the putative pro-survival Bcl-2 homolog BHP2, which protects sponge tissue as well as mammalian Hek-293 and NIH-3T3 cells against diverse apoptotic stimuli. The Lake Baikal demosponge Lubomirskia baicalensis has been shown to encode both putative pro-survival Bcl-2 (LB-Bcl-2) and pro-apoptotic Bcl-2 members (LB-Bak-2), which have been implied in axis formation (branches) in L...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28079889/deletion-of-the-bh3-only-protein-noxa-alters-electrographic-seizures-but-does-not-protect-against-hippocampal-damage-after-status-epilepticus-in-mice
#2
Naoki Ichikawa, Mariana Alves, Shona Pfeiffer, Elena Langa, Yasmina E Hernández-Santana, Hidenori Suzuki, Jochen Hm Prehn, Tobias Engel, David C Henshall
Several members of the Bcl-2 gene family are dysregulated in human temporal lobe epilepsy and animal studies show that genetic deletion of some of these proteins influence electrographic seizure responses to chemoconvulsants and associated brain damage. The BH3-only proteins form a subgroup comprising direct activators of Bax-Bak that are potently proapoptotic and a number of weaker proapoptotic BH3-only proteins that act as sensitizers by neutralization of antiapoptotic Bcl-2 family members. Noxa was originally characterized as a weaker proapoptotic, 'sensitizer' BH3-only protein, although recent evidence suggests it too may be potently proapoptotic...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28078995/sphingolipids-in-genetic-and-acquired-forms-of-chronic-kidney-diseases
#3
Norishi Ueda
Sphingolipids (SLs) regulate apoptosis, proliferation, and stress response. SLs, including ceramide, glycosphingolipids (glucosylceramide, lactosylceramide, and gangliosides) and sphingosine-1-phosphate (S1P), play a role in the pathogenesis and progression of genetic (lysosomal storage disease, congenital nephrotic syndrome and polycystic kidney disease) and non-genetic forms of chronic kidney diseases (CKDs). SLs metabolism defects promote complications (cardiovascular events, etc.) via oxidant stress in CKDs...
January 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28069133/bh3-only-proteins-in-health-and-disease
#4
J A Glab, G W Mbogo, H Puthalakath
BH3-only proteins are proapoptotic members of the broader Bcl-2 family, which promote cell death by directly or indirectly activating Bax and Bak. The expression of BH3-only proteins is regulated both transcriptionally and posttranscriptionally in a cell type-specific and a tissue-specific manner. Research over the last 20 years has provided significant insights into their roles in tissue homeostasis and various pathologies, which in turn has led to the development of novel therapeutics for numerous diseases...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28064468/the-membrane-activity-of-bok-involves-formation-of-large-stable-toroidal-pores-and-is-promoted-by-cbid
#5
Yuniel Fernández-Marrero, Stephanie Bleicken, Kushal Kumar Das, Daniel Bachmann, Thomas Kaufmann, Ana J Garcia-Saez
The BCL-2 family members are key regulators of the intrinsic apoptotic pathway, which is defined by permeabilisation of the mitochondrial outer membrane by members of the BAX-like subfamily. BOK is classified as a BAX-like protein; however, its (patho-)physiological role remains largely unclear. We therefore assessed the membrane permeabilisation potential of C-terminally truncated recombinant BOK, BOK(∆C) . We show that BOK(∆C) can permeabilize liposomes mimicking the composition of mitochondrial outer membrane, but not of endoplasmic reticulum, forming large and stable pores over time...
January 8, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28061447/the-combination-effect-of-homoharringtonine-and-ibrutinib-on-flt3-itd-mutant-acute-myeloid-leukemia
#6
Xia Li, Xiufeng Yin, Huafeng Wang, Jiansong Huang, Mengxia Yu, Zhixin Ma, Chenying Li, Yile Zhou, Xiao Yan, ShuJuan Huang, Jie Jin
Acute myeloid leukemia (AML) is a highly heterogeneous disease and internal tandem duplication mutation in FMS-like tyrosine-kinase-3 (FLT3-ITD) has a negative impact on outcome. Finding effective treatment regimens is desperately needed. In this study, we explored the inhibitory effect and mechanism of homoharringtonine (HHT) in combination with ibrutinib on FLT3-ITD mutant AML cells. Consequently, we observed a synergistic inhibitory effect when ibrutinib was combined with HHT to inhibit cell proliferation, induce apoptosis and arrest cell cycle at G0/G1 phase in MV4-11 and MOLM-13 leukemia cells...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28053104/structural-insight-into-african-swine-fever-virus-a179l-mediated-inhibition-of-apoptosis
#7
Suresh Banjara, Sofia Caria, Linda K Dixon, Mark G Hinds, Marc Kvansakul
: Programmed cell death is a tightly controlled process critical for the removal of damaged or infected cells. Pro- and anti-apoptotic proteins of the Bcl-2 family are pivotal mediators of this process. African Swine Fever virus (ASFV) is a large DNA virus, the only member of the Asfarviridae family, and harbors A179L, a putative Bcl-2 like protein. A179L has been shown to bind to several pro-apoptotic Bcl-2 proteins, however the hierarchy of binding and the structural basis for apoptosis inhibition are currently not understood...
January 4, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28049729/the-plant-hormone-abscisic-acid-is-a-pro-survival-factor-in-human-and-murine-megakaryocytes
#8
Alessandro Malara, Chiara Fresia, Christian Andrea Di Buduo, Paolo Maria Soprano, Francesco Moccia, Cesare Balduini, Elena Zocchi, Antonio De Flora, Alessandra Balduini
Abscisic acid (ABA) is a phytohormone involved in pivotal physiological functions in higher plants. Recently, ABA proved to be secreted and active also in mammals, where it stimulates the activity of innate immune cells, of mesenchymal and hematopoietic stem cells and of insulin-releasing pancreatic β-cells through a signaling pathway involving the second messenger cyclic ADP-ribose (cADPR). In addition to behaving as an animal hormone, ABA holds promise also as nutraceutical plant-derived compound in humans...
January 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28044240/insulin-like-growth-factor-binding-protein6-associated-with%C3%A2-neuronal-apoptosis-following-intracerebral-hemorrhage-in-rats
#9
Qijun Dai, Peipei Jiang, Yang Gu, Lin Zhu, Haifeng Dai, Zhigang Yao, Hua Liu, Xiaoping Ma, Chengwei Duan, Lianxia Qu
The insulin-like growth factor (IGF) system is linked to CNS pathological states. The functions of IGFs are modulated by a family of binding proteins termed insulin-like growth factor binding proteins (IGFBPs). Here, we demonstrate that IGFBP-6 may be associated with neuronal apoptosis in the processes of intracerebral hemorrhage (ICH). We obtained a significant upregulation of IGFBP-6 in neurons adjacent to the hematoma following ICH with the results of Western blot, immunohistochemistry, and immunofluorescence...
January 2, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28040547/lemur-tyrosine-kinase-2-lmtk2-is-a-determinant-of-cell-sensitivity-to-apoptosis-by-regulating-the-levels-of-the-bcl2-family-members
#10
Annalisa Conti, Maria Teresa Majorini, Enrico Fontanella, Alberto Bardelli, Mauro Giacca, Domenico Delia, Miguel Mano, Daniele Lecis
Using a high-throughput approach, we identified lemur tyrosine kinase 2 (LMTK2) as a novel determinant of cell sensitivity to TRAIL. LMTK2 is a poorly characterized serine/threonine kinase believed to play a role in endosomal membrane trafficking and neuronal physiology, and recently found to be mutated in diverse tumor types. We show that LMTK2 silencing sensitizes immortalized epithelial cells and cancer cells to TRAIL, and this phenomenon is accompanied by changes in the expression of BCL2 family members...
December 29, 2016: Cancer Letters
https://www.readbyqxmd.com/read/28039357/key-survival-factor-mcl-1-correlates-with-sensitivity-to-combined-bcl-2-bcl-xl-blockade
#11
Michelle Williams, Linus Lee, Donna J Hicks, Meghan M Joly, David Elion, Bushra Rahman, Courtney McKernan, Violeta Sanchez, Justin M Balko, Thomas Stricker, Monica Valeria Estrada, Rebecca S Cook
: An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use anti-apoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of anti-apoptotic Bcl-2 family members in clinical breast cancer datasets, revealed greater expression and more frequent gene amplification of MCL1 as compared to BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like...
December 30, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28035994/obatoclax-a-pan-bcl-2-inhibitor-targets-cyclin-d1-for-degradation-to-induce-antiproliferation-in-human-colorectal-carcinoma-cells
#12
Chi-Hung R Or, Yachu Chang, Wei-Cheng Lin, Wee-Chyan Lee, Hong-Lin Su, Muk-Wing Cheung, Chang-Po Huang, Cheesang Ho, Chia-Che Chang
Colorectal cancer is the third most common cancer worldwide. Aberrant overexpression of antiapoptotic BCL-2 (B-cell lymphoma 2) family proteins is closely linked to tumorigenesis and poor prognosis in colorectal cancer. Obatoclax is an inhibitor targeting all antiapoptotic BCL-2 proteins. A previous study has described the antiproliferative action of obatoclax in one human colorectal cancer cell line without elucidating the underlying mechanisms. We herein reported that, in a panel of human colorectal cancer cell lines, obatoclax inhibits cell proliferation, suppresses clonogenicity, and induces G₁-phase cell cycle arrest, along with cyclin D1 downregulation...
December 27, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28032645/arabidopsis-b-cell-lymphoma2-bcl-2-associated-athanogene-7-bag7-mediated-heat-tolerance-requires-translocation-sumoylation-and-binding-to-wrky29
#13
Yurong Li, Brett Williams, Martin Dickman
To cope with stress and increased accumulation of misfolded proteins, plants and animals use a survival pathway known as the unfolded protein response (UPR) that signals between the endoplasmic reticulum (ER) and the nucleus to maintain cell homeostasis via proper folding of proteins. B-cell lymphoma2 (Bcl-2)-associated athanogene (BAG) proteins are an evolutionarily conserved family of co-chaperones that are linked to disease states in mammals and responses to environmental stimuli (biotic and abiotic) in plants...
December 29, 2016: New Phytologist
https://www.readbyqxmd.com/read/28024402/relative-binding-free-energy-calculations-applied-to-protein-homology-models
#14
Daniel Cappel, Michelle Lynn Hall, Eelke B Lenselink, Thijs Beuming, Jun Qi, James Bradner, Woody Sherman
A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein-ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters)...
December 27, 2016: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28009968/the-dielectrophoretic-disassociation-of-chloride-ions-and-the-influence-on-diamagnetic-anisotropy-in-cell-membranes
#15
Marcy C Purnell, Terence J Skrinjar
Chloride channels represent ubiquitously expressed proteins that regulate fundamental cellular processes including membrane potential, maintenance of intracellular pH, and regulation of cell volume. However, mechanisms to modulate this large family of ion channels have remained elusive to date. This large chloride channel family does not appear to operate with selectivity similar to the sodium and potassium channels. These unique channels appear to be bi-directional cotransporters of two or more different molecules or ions across a bilayer phospholipid membrane...
November 2016: Discovery Medicine
https://www.readbyqxmd.com/read/28009301/tight-sequestration-of-bh3-proteins-by-bcl-xl-at-subcellular-membranes-contributes-to-apoptotic-resistance
#16
Jessie Pécot, Laurent Maillet, Janic Le Pen, Céline Vuillier, Sophie de Carné Trécesson, Aurélie Fétiveau, Kristopher A Sarosiek, Florian J Bock, Frédérique Braun, Anthony Letai, Stephen W G Tait, Fabien Gautier, Philippe P Juin
Anti-apoptotic BCL-2 family members bind to BH3-only proteins and multidomain BAX/BAK to preserve mitochondrial integrity and maintain survival. Whereas inhibition of these interactions is the biological basis of BH3-mimetic anti-cancer therapy, the actual response of membrane-bound protein complexes to these compounds is currently ill-defined. Here, we find that treatment with BH3 mimetics targeting BCL-xL spares subsets of cells with the highest levels of this protein. In intact cells, sequestration of some pro-apoptotic activators (including PUMA and BIM) by full-length BCL-xL is much more resistant to derepression than previously described in cell-free systems...
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/28008641/effects-of-mirnas-on-myocardial-apoptosis-by-modulating-mitochondria-related-proteins
#17
REVIEW
Yanfang Zhao, Murugavel Ponnusamy, Yanhan Dong, Lei Zhang, Kun Wang, Peifeng Li
Myocardial apoptosis play a vital role in pathogenesis of cardiovascular diseases. The intrinsic pathway of apoptosis (mitochondrial apoptosis pathway) and abnormal mitochondrial fission and fusion have a detrimental effect on cells under a variety of intracellular stresses including hypoxia, oxidative stress, drug toxicity or DNA damage and contributes to the development of heart failure (HF), myocardial infarction (MI), diabetic cardiomyopathy and ischemia/reperfusion injury (I/R). MicroRNAs (miRNAs) are endogenous short noncoding RNAs, which target 3'-untranslated region of mRNA to switch off gene expression...
December 23, 2016: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28002618/verteporfin-suppresses-cell-survival-angiogenesis-and-vasculogenic-mimicry-of-pdac-via-disrupting-the-yap-tead-complex
#18
Honglong Wei, Fuhai Wang, Yong Wang, Tao Li, Peng Xiu, Jingtao Zhong, Xueying Sun, Jie Li
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. The Yes-associated protein-1 (YAP) plays a critical role in cell proliferation, apoptosis and angiogenesis. Verteporfin is a photosensitizer used in photodynamic therapy and also a small molecular inhibitor of the Hippo-YAP pathway. However, little is known whether verteporfin could inhibit YAP activity in PDAC cells. Our present results showed that verteporfin suppressed the proliferation of human PDAC PANC-1 and SW1990 cells by arresting cells at G1 phase, and inducing apoptosis in dose- and time-dependent manners...
December 21, 2016: Cancer Science
https://www.readbyqxmd.com/read/28002605/knockdown-of-the-putative-lifeguard-homologue-cg3814-in-neurons-of-drosophila-melanogaster
#19
P G M'Angale, B E Staveley
Lifeguard is an integral transmembrane protein that modulates FasL-mediated apoptosis by interfering with the activation of caspase 8. It is evolutionarily conserved, with homologues present in plants, nematodes, zebra fish, frog, chicken, mouse, monkey, and human. The Lifeguard homologue in Drosophila, CG3814, contains the Bax inhibitor-1 family motif of unknown function. Downregulation of Lifeguard disrupts cellular homeostasis and disease by sensitizing neurons to FasL-mediated apoptosis. We used bioinformatic analyses to identify CG3814, a putative homologue of Lifeguard, and knocked down CG3814/LFG expression under the control of the Dopa decarboxylase (Ddc-Gal4) transgene in Drosophila melanogaster neurons to investigate whether it possesses neuroprotective activity...
December 19, 2016: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/27999336/debouganin-diabody-fusion-protein-overcomes-drug-resistance-to-adcs-comprised-of-anti-microtubule-agents
#20
Shilpa Chooniedass, Rachelle L Dillon, Arjune Premsukh, Peter J Hudson, Gregory P Adams, Glen C MacDonald, Jeannick Cizeau
Antibody drug conjugates (ADC), comprised of highly potent small molecule payloads chemically conjugated to a full-length antibody, represent a growing class of therapeutic agents. The targeting of cytotoxic payloads via the specificity and selectivity of the antibody has led to substantial clinical benefits. However, ADC potency can be altered by mechanisms of resistance such as overexpression of efflux pumps or anti-apoptotic proteins. DeBouganin is a de-immunized variant of bouganin, a ribosome-inactivating protein (RIP) that blocks protein synthesis, thereby leading to apoptosis...
December 17, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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