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Bcl-2 family proteins

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https://www.readbyqxmd.com/read/28333095/cytosolic-bnip3-dimer-interacts-with-mitochondrial-bax-forming-heterodimers-in-the-mitochondrial-outer-membrane-under-basal-conditions
#1
Ulrike B Hendgen-Cotta, Sonja Esfeld, Katharina Rudi, Ilkka Miinalainen, Johann P Klare, Tienush Rassaf
The primary function of mitochondria is energy production, a task of particular importance especially for cells with a high energy demand like cardiomyocytes. The B-cell lymphoma (BCL-2) family member BCL-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is linked to mitochondrial targeting after homodimerization, where it functions in inner membrane depolarization and permeabilization of the mitochondrial outer membrane (MOM) mediating cell death. We investigated the basal distribution of cardiac BNIP3 in vivo and its physical interaction with the pro-death protein BCL2 associated X, apoptosis regulator (BAX) and with mitochondria using immunoblot analysis, co-immunoprecipitation, and continuous wave and pulsed electron paramagnetic resonance spectroscopy techniques...
March 23, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28319809/abt-737-synergizes-with-cisplatin-bypassing-aberration-of-apoptotic-pathway-in-non-small-cell-lung-cancer
#2
Eun Young Kim, Ji Ye Jung, Arum Kim, Yoon Soo Chang, Se Kyu Kim
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models...
March 17, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28315432/splicing-factors-of-sr-and-hnrnp-families-as-regulators-of-apoptosis-in-cancer
#3
Hanna Kędzierska, Agnieszka Piekiełko-Witkowska
SR and hnRNP proteins were initially discovered as regulators of alternative splicing: the process of controlled removal of introns and selective joining of exons through which multiple transcripts and, subsequently, proteins can be expressed from a single gene. Alternative splicing affects genes involved in all crucial cellular processes, including apoptosis. During cancerogenesis impaired apoptotic control facilitates survival of cells bearing molecular aberrations, contributing to their unrestricted proliferation and chemoresistance...
March 14, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28315370/control-of-mitochondrial-physiology-and-cell-death-by-the-bcl-2-family-proteins-bax-and-bok
#4
Beatrice D'Orsi, Julia Mateyka, Jochen H M Prehn
Neuronal cell death is often triggered by events that involve intracellular increases in Ca(2+). Under resting conditions, the intracellular Ca(2+) concentration is tightly controlled by a number of extrusion and sequestering mechanisms involving the plasma membrane, mitochondria, and ER. These mechanisms act to prevent a disruption of neuronal ion homeostasis. As these processes require ATP, excessive Ca(2+) overloading may cause energy depletion, mitochondrial dysfunction, and may eventually lead to Ca(2+)-dependent cell death...
March 14, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28315173/ricolinostat-a-selective-hdac6-inhibitor-shows-anti-lymphoma-cell-activity-alone-and-in-combination-with-bendamustine
#5
Maria Cosenza, Monica Civallero, Luigi Marcheselli, Stefano Sacchi, Samantha Pozzi
Histone deacetylase inhibitors (HDACis) have emerged as a new class of anticancer agents, targeting the biological process including cell cycle and apoptosis. We investigated and explained the anticancer effects of an HDAC6 inhibitor, ricolinostat alone and in combination with bendamustine in lymphoma cell lines. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) generation, Bcl-2 protein expression, cell cycle progression and tubuline expression were determined by flow cytometry...
March 17, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28301598/regulation-of-anti-apoptotic-bcl-2-family-protein-mcl-1-by-s6-kinase-2
#6
Alakananda Basu, Savitha Sridharan
The anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance. We have previously shown that knockdown of the 40S ribosomal protein S6 kinase-2 (S6K2), which acts downstream of the mechanistic target of rapamycin complex 1 (mTORC1), enhanced breast cancer cell death by apoptotic stimuli. The increase in cell death by S6K2 depletion was partly due to inactivation of Akt. In the present study, we investigated if S6K2 regulates Mcl-1, which acts downstream of Akt...
2017: PloS One
https://www.readbyqxmd.com/read/28300289/dehydrocostus-lactone-suppresses-proliferation-of-human-chronic-myeloid-leukemia-cells-through-bcr-abl-jak-stat-signaling-pathways
#7
Hong Cai, Xiaosong Qin, Chunhui Yang
This study evaluates the anticancer effects of dehydrocostus lactone, a plant-derived sesquiterpene lactone, on human chronic myeloid leukemia cells. Dehydrocostus lactone significantly inhibits cell proliferation by inducing cells to undergo cell cycle arrest, apoptosis and differentiation. Dehydrocostus lactone suppresses the expression of cyclin B1, cyclin A, cyclin E, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 1 (CDK2) and increases p21 expression, resulting in S-G2/M phase arrest in K562 cells...
March 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28288819/multifaceted-anticancer-activity-of-bh3-mimetics-current-evidence-and-future-prospects
#8
REVIEW
Małgorzata Opydo-Chanek, Oscar Gonzalo, Isabel Marzo
BH3 mimetics are a novel class of anticancer agents designed to specifically target pro-survival proteins of the Bcl-2 family. Like endogenous BH3-only proteins, BH3 mimetics competitively bind to surface hydrophobic grooves of pro-survival Bcl-2 family members, counteracting their protective effects and thus facilitating apoptosis in cancer cells. Among the small-molecule BH3 mimetics identified, ABT-737 and its analogs, obatoclax as well as gossypol derivatives are the best characterized. The anticancer potential of these compounds applied as a single agent or in combination with chemotherapeutic drugs is currently being evaluated in preclinical studies and in clinical trials...
March 10, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28283400/vdac-in-cancer
#9
REVIEW
N M Mazure
The voltage-dependent anion channel (VDAC) is a pore located at the outer membrane of the mitochondrion. It allows the entry and exit of numerous ions and metabolites between the cytosol and the mitochondrion. Flux through the pore occurs in an active way: first, it depends on the open or closed state and second, on the negative or positive charges of the different ion species passing through the pore. The flux of essential metabolites, such as ATP, determines the functioning of the mitochondria to a noxious stimulus...
March 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28279820/binding-affinity-of-pro-apoptotic-bh3-peptides-for-the-anti-apoptotic-mcl-1-and-a1-proteins-molecular-dynamics-simulations-of-mcl-1-and-a1-in-complex-with-six-different-bh3-peptides
#10
Vivek Modi, Ramasubbu Sankararamakrishnan
The anti-apoptotic members of Bcl-2 family of proteins bind to their pro-apoptotic counterparts to induce or prevent cell death.Based on the distinct binding profiles for specific pro-apoptotic BH3 peptides, the anti-apoptotic Bcl-2 proteins can be divided into at least two subclasses. The subclass that includes Bcl-XL binds strongly to Bad BH3 peptide while it has weak binding affinity for the second subclass of Bcl-2 proteins such as Mcl-1 and A1. Anti-apoptotic Bcl-2 proteins are considered to be attractive drug targets for anti-cancer drugs...
February 9, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28277671/enzyme-cleavable-polymeric-micelles-for-the-intracellular-de-livery-of-pro-apoptotic-peptides
#11
Hanna B Kern, Selvi Srinivasan, Anthony J Convertine, David Hockenbery, Oliver W Press, Patrick S Stayton
Peptides derived from the third Bcl-2 homology domain (BH3) renormalize apoptotic signaling by antagonizing pro-survival Bcl-2 family members. They serve as a model for potential peptide drugs that possess therapeutic activities but are limited by delivery barriers including short circulation half-lives and poor penetration into cells. A diblock polymeric micelle carrier for the BIM BH3 peptide was recently described that demonstrated anti-tumor activity in a B-cell lymphoma xenograft model [Berguig et al., Mol Ther, 2015]...
March 9, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28275031/nccn-guidelines-insights-chronic-lymphocytic-leukemia-small-lymphocytic-leukemia-version-1-2017
#12
William G Wierda, Andrew D Zelenetz, Leo I Gordon, Jeremy S Abramson, Ranjana H Advani, C Babis Andreadis, Nancy Bartlett, John C Byrd, Paolo Caimi, Luis E Fayad, Richard I Fisher, Martha J Glenn, Thomas M Habermann, Nancy Lee Harris, Francisco Hernandez-Ilizaliturri, Richard T Hoppe, Steven M Horwitz, Mark S Kaminski, Christopher R Kelsey, Youn H Kim, Susan Krivacic, Ann S LaCasce, Michael G Martin, Auayporn Nademanee, Pierluigi Porcu, Oliver Press, Rachel Rabinovitch, Nishitha Reddy, Erin Reid, Kenneth Roberts, Ayman A Saad, Erin D Snyder, Lubomir Sokol, Lode J Swinnen, Julie M Vose, Joachim Yahalom, Mary A Dwyer, Hema Sundar
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL...
March 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28265066/resistance-mechanisms-to-tp53-mdm2-inhibition-identified-by-in-vivo-piggybac-transposon-mutagenesis-screen-in-an-arf-mouse-model
#13
Emilie A Chapeau, Agnieszka Gembarska, Eric Y Durand, Emeline Mandon, Claire Estadieu, Vincent Romanet, Marion Wiesmann, Ralph Tiedt, Joseph Lehar, Antoine de Weck, Roland Rad, Louise Barys, Sebastien Jeay, Stephane Ferretti, Audrey Kauffmann, Esther Sutter, Armelle Grevot, Pierre Moulin, Masato Murakami, William R Sellers, Francesco Hofmann, Michael Rugaard Jensen
Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201...
March 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28264627/natural-polyphenolic-inhibitors-against-the-antiapoptotic-bcl-2
#14
Sharad Verma, Aditi Singh, Anchala Kumari, Chetna Tyagi, Sukriti Goyal, Salma Jamal, Abhinav Grover
The apoptotic mechanism is regulated by the BCL-2 family of proteins, such as BCL-2 or Bcl-xL, which block apoptosis while Bad, Bak, Bax, Bid, Bim or Hrk induce apoptosis. The overexpression of BCL-2 was found to be related to the progression of cancer and also providing resistance towards chemotherapeutic treatments. In the present study, we found that all polyphenols (apigenin, fisetin, galangin and luteolin) bind to the hydrophobic groove of BCL-2 and the interaction is stable throughout MD simulation run...
March 6, 2017: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/28262002/there-is-something-about-bok-we-just-don-t-get-yet
#15
Manuel D Haschka, Andreas Villunger
Fernández-Marrero and colleagues show in their work that the proapoptotic BCL-2 family member BOK can form large, stable pores in artificial liposomes. This can be enhanced by the proapoptotic protein cBID and is unaffected by the antiapoptotic BCL-XL . Although BOK can bind to isolated mitochondria, it is unable to cause cytochrome c release even with the help of cBID.
March 2017: FEBS Journal
https://www.readbyqxmd.com/read/28261909/angiotensin-ii-degrades-myeloid-cell-leukemia-1-in-human-umbilical-vein-endothelial-cells
#16
Wenlong Zhang, Ruyan Yang, Yaorong Feng, Bin Hu, Jun Zhang, Qian Zhang, Ningning Rong
Angiotensin II (Ang II) plays a central role in cardiovascular diseases by causing endothelial apoptosis and dysfunction. Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of apoptosis-regulating proteins. It has been reported that Mcl-1 plays a pivotal role in protecting cells against apoptosis. Presently, the effects of Ang II on the expression of Mcl-1 remain unknown. In this study, we report, for the first time, that the antiapoptotic protein Mcl-1 is degraded by the proteasome during Ang II-induced apoptosis in HUVECs...
March 5, 2017: IUBMB Life
https://www.readbyqxmd.com/read/28259821/inhibition-of-mapkinase-pathway-sensitizes-thyroid-cancer-cells-to-abt-737-induced-apoptosis
#17
Viswanath Gunda, Kristopher A Sarosiek, Eran Brauner, Yon Seon Kim, Salma Amin, Zhiheng Zhou, Antony Letai, Sareh Parangi
Bcl2 family proteins play an important role in the resistance of thyroid cancer cells to apoptosis induced by chemotherapeutic drugs and targeted therapies. BH3-profiling of seven fresh primary papillary thyroid cancer (PTC) tumors showed dependence for survival on Bcl-xL (2/7), Bcl2 (2/7), and Mcl-1 (2/7), while the majority of thyroid cell lines were mainly dependent on Bcl-xL. Targeting Bcl2 family proteins with the BH3 mimetic, ABT-737, while simultaneously inhibiting ERK pathway proteins with PLX4720 and PD325901 was shown to induce significantly high apoptosis in the majority of cell lines (8505c, SW1736, HTh7, BCPAP) and moderate apoptosis in the TPC-1 cell line...
March 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28255309/effects-of-doxepin-on-gene-expressions-of-bcl-2-family-tnf-%C3%AE-map-kinase-14-and-akt1-in-the-hippocampus-of-rats-exposed-to-stress
#18
Parham Reisi, Nastaran Eidelkhani, Laleh Rafiee, Mohammad Kazemi, Maryam Radahmadi, Hojjatallah Alaei
Stress is one of the effective factors in the development of depressive disorders that performs some parts of its effects by affecting hippocampus. Since doxepin has been shown to have neuroprotective effects, in this study, we focused on the effects of doxepin on the expression of involved genes in neuronal survival and plasticity in the rat hippocampus following chronic stress. Male Wistar rats were divided into four groups, the control, the stress, the stress-doxepin 1 mg/kg and the stress-doxepin 5 mg/kg, respectively...
February 2017: Research in Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28252652/bh3-mimetic-elicited-ca-2-signals-in-pancreatic-acinar-cells-are-dependent-on-bax-and-can-be-reduced-by-ca-2-like-peptides
#19
Pawel E Ferdek, Monika A Jakubowska, Polina Nicolaou, Julia V Gerasimenko, Oleg V Gerasimenko, Ole H Petersen
BH3 mimetics are small-molecule inhibitors of B-cell lymphoma-2 (Bcl-2) and Bcl-xL, which disrupt the heterodimerisation of anti- and pro-apoptotic Bcl-2 family members sensitising cells to apoptotic death. These compounds have been developed as anti-cancer agents to counteract increased levels of Bcl-2 proteins often present in cancer cells. Application of a chemotherapeutic drug supported with a BH3 mimetic has the potential to overcome drug resistance in cancers overexpressing anti-apoptotic Bcl-2 proteins and thus increase the success rate of the treatment...
March 2, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28248443/iron-overload-induces-apoptosis-of-murine-preosteoblast-cells-via-ros-and-inhibition-of-akt-pathway
#20
Jun-Yu Ke, Wan-Jing Cen, Xue-Zhong Zhou, Ye-Rong Li, Wei-Dong Kong, Jian-Wei Jiang
OBJECTIVE: This study investigates the inhibitory effect of iron overload on MC3T3-E1 cells and its molecular mechanism. METHODS: MC3T3-E1 cells were grown under different concentrations of FAC (ferric ammonium citrate), the WST-8 assay was used to investigate the proliferation of cells following FAC with or without deferasirox. DCFH-DA fluorescence probe was applied to detect the cellular reactive oxygen species (ROS) level. The apoptotic cells were analyzed with Annexin V-FITC/PI and the Hoechst 33258 nuclear staining assay...
March 1, 2017: Oral Diseases
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