DOCSLIB.ORG

Thirty Years of BCL-2: Translating Cell Death Discoveries Into Novel Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Thirty Years of BCL-2: Translating Cell Death Discoveries Into Novel Cancer PERSPECTIVES normal physiology and cancer remains TIMELINE unclear, and is beyond the scope of this article (for a review on these topics, see Thirty years of BCL-2: translating REF. 10). This Timeline article focuses on key advances in our understanding of the function of the BCL-2 protein family in cell death discoveries into novel cell death, in the development of cancer, cancer therapies and as targets in cancer therapy. Early studies on apoptosis Alex R. D. Delbridge, Stephanie Grabow, Andreas Strasser and David L. Vaux In their 1972 paper that adopted the word ‘apoptosis’ to describe a physiological Abstract | The ‘hallmarks of cancer’ are generally accepted as a set of genetic and process of cellular suicide, Kerr and epigenetic alterations that a normal cell must accrue to transform into a fully colleagues11 recognized the presence malignant cancer. It follows that therapies designed to counter these alterations of apoptotic cells in tissue sections of miht e effective as anti-cancer strateies ver the past 3 years, research on certain human cancers. Accordingly, the BCL-2-regulated apoptotic pathway has led to the development of they proposed that increasing the rate of apoptosis of neoplastic cells relative to their small-molecule compounds, nown as BH3-mimetics, that ind to pro-survival rate of production could potentially be BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline therapeutic. However, interest in cell death article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and its role in cancer languished until the and, specifically, its roles in cancer development and therapy late 1980s, when genetic abnormalities that prevented cell death were directly linked to malignancy in humans. In the past 30 years, cell death has become and established a new hallmark of Until the early 1980s, most oncogenes a major field of investigation, building cancer2 — evasion of cell death were discovered as genes carried by to a crescendo with the recent award of (apoptosis) (FIG. 1). transforming retroviruses (for example, ‘Breakthrough Therapy Designation’ from Over the past three decades, research v-myc, v-src and v-abl), genes located at the US Food and Drug Administration in hundreds of laboratories has identified recurrent chromosomal translocation (FDA) to ABT-199 (also known as and characterized at least 16 members break points (for example, BCR–ABL venetoclax), a selective inhibitor of of the BCL-2 protein family, and and MYC), or genes that could transfer the anti-apoptotic protein BCL-2, in categorized them into three functional oncogenic properties from malignant recognition of its promise as a treatment groups that each bear one or more cells to non-malignant ones (for example, for patients with chemotherapy- resistant BCL-2 homology (BH) domains (FIG. 2). mutant RAS)12. Whereas the normal chronic lymphocytic leukaemia (CLL)1. These are the pro-survival BCL-2 family counterparts of these oncogenes promoted Although research on cell death members (including BCL-2 itself), cell proliferation in a controlled manner, extends back more than 150 years, the multi-BH-domain pro-apoptotic when they were dysregulated in cancers, until the late 1980s it remained an members (such as BAX and BAK) and they caused uncontrolled cell growth esoteric subject. Today, however, it is the pro-apoptotic ‘BH3-only’ proteins and proliferation. a major research field, with more than (such as BIM (also known as BCL2L11) 20,000 new publications on apoptosis and PUMA (also known as BBC3)). Many BCL2: a novel class of oncogene or programmed cell death appearing of the upstream pathways that control The discovery of BCL-2 started with the each year. The explosion in interest was these proteins have been elucidated, as association of t(14;18) chromosomal sparked by research on one protein, well as the effector processes triggered translocations with human follicular BCL-2, as experiments on BCL-2 showed by their activation that are the ultimate lymphoma by Fukuhara and Rowley13. that mechanisms for cell death are highly cause of cell demolition. Reviews that This enabled others to clone the conserved throughout the evolution provide detailed in-depth discussion of chromosomal break point, and of animals, and because chromosomal BCL-2-regulated apoptosis signalling at a subsequently the cDNA, of a gene on translocations that activate the BCL2 gene molecular level are available3–9. Although chromosome 18, which was termed BCL2 are associated with malignant disease in non-apoptotic roles for BCL-2 family for B cell leukaemia or lymphoma gene humans. Thus, the identification of BCL-2 members have been investigated, including number 2 (REFS 14–18). as an inhibitor of cell death marked roles in autophagy, endoplasmic reticulum The strong association of translocations recognition of the first component of a (ER) calcium dynamics and the unfolded involving BCL2 with follicular lymphoma cell death mechanism in any organism, protein response, their importance in suggested that it was an oncogene, but NATURE REVIEWS | CANCER VOLUME 16 | FEBRUARY 2016 | 99 © 2016 Macmillan Publishers Limited. All rights reserved PERSPECTIVES • Cloning of human MCL1 (REF. 57) BAX loss of Bim-knockout mice show that • Cloning of mouse A1 (REF. 59) function mutations Discovery that platelets • ABT-199 granted BH3-only proteins are essential require BCL-X for survival176 • Cloning of chicken, human and reported in L Genetic analysis to breakthrough 58 for initiation of apoptosis in at mouse BCLX • Two distinct pathways, one haematopoietic least some circumstances97 determine which therapy designa- Identification of cell death • Cloning of human BAX62 regulated by BCL-2 and the cancers and in Inhibitors of oncogenic kinases pro-survival BCL-2 family tion by the US FDA1 t(14;18) inhibitory function of BCL-2, • BCL-2 can block death in cells other by ‘death receptors’, colon cancer with kill tumour cells by activating member is needed for • Phase I clinical trial translocation its oncogenic activity and its Subcellular localization lacking mitochondrial DNA34 can lead to apoptosis47 a hypermutation Roles of BH3-only proteins BIM, and this killing is enhanced sustained growth of results for ABT-199 identified13 ability to synergize with MYC21 of BCL-2 resolved30,33–35 • Bcl2-knockout mice created83,85 • Cloning of mouse Bad67 phenotype142,143 determined97,145,146,193,194 by BH3-mimetic compounds150,151 cancer186–190 reported180 1978 1984 1986 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2003 2004 2005 2006 2007 2010 2013 2014 2015 Cloning of the t(14;18) break • BCL2 transgenic mice BCL-2 inhibits • BCL-2 and CED-9 • Cloning of mouse Bid • Discovery of BIM76 • Loss of BIM rescues developmental • Different BH3-only Development and point involving BCL2 (REF. 14) developed22 cell killing are sequence and development of • Two CD95 (also defects in BCL-2-deficient mice86 proteins have different first clinical trials with • BCL-2 protects against a induced by homologues53 the BH3-only protein known as APO-1 • Discovery of human PUMA79,80 abilities to bind to ABT-199 reported179 wide range of cytotoxic anti-cancer • Requirement for a concept; evidence or FAS) signalling different pro-survival Cloning of human 25 28,29 88 16,17 stress agents drugs mitochondrial for direct activation pathways, only • Mcl1 knockout mice created BCL-2 family BCL2 cDNA 72,74 component shown in of BAX by a BH3-only one of which can • Discovery of mouse NOXA78 members Clinical trial results a cell-free system of protein70 be inhibited by • Bax and Bak double knockout mice developed; • Development of with ABT-263 first Synergy of defects in apoptosis apoptosis113 BCL-2, identified48 BH3-mimetics168 reported171 • Structure of BCL-XL demonstration that BAX and BAK have and cell proliferation control in reported167 107 lymphomagenesis demonstrated essential overlapping roles in apoptosis in vivo36 • Not all apoptosis is blocked by BCL-2 (REF. 46) • Discovery that BCL-2 inhibits mitochondrial release • BCL-2 is a functional of cytochrome c and of the role of cytochrome c in homologue of Caenorhabditis activation of the caspase cascade115,116 elegans CED-9 (REF. 52) • Translocation of BAX to mitochondria117 • Inhibition of BAX channels by BCL-2 (REF. 118) Figure 1 | Timeline of key discoveries. This timeline descries ey discoveries related to the identification of BCL-2, determination of its function, its role Nature Reviews | Cancer and that of other BCL-2 family memers in cancer, and efforts to taret BCL-2 family memers for the treatment of cancer DA, ood and Dru Administration CL, myeloid cell leuaemia did not constitute proof, and the amino Although BCL-2 was originally death alone was not sufficient to render a acid sequence did not provide clues reported to reside on the cytosolic face of cell fully transformed. In 1983, Land et al.39 to its function. Because expression of intracellular membranes30,31, subsequent had shown that transformation of fibroblasts several known oncogenes, including articles suggested that it is localized to required expression not only of a RAS SV40 large T antigen, v-abl and v-fms, the inner mitochondrial membrane26 or the oncogene, but also of MYC. Furthermore, enabled interleukin-3 (IL-3)-dependent plasma membrane32. This was resolved by in a patient, Croce et al.40 had observed the mouse myeloid FDC-P1 cells to grow Monaghan et al.33, Jacobson et al.34 and transformation of a follicular lymphoma in the absence of that cytokine, and to Lithgow et al.35 who showed that the first bearing a BCL2 translocation into acute form tumours in mice (see, for example, reports were correct, and that BCL-2 resides pre-B cell leukaemia after acquisition REFS 19,20), a BCL2 expression construct on the outer mitochondrial membrane, the of a second chromosomal translocation was transduced into these cells and they ER membrane and the nuclear envelope, involving MYC.
Load more

Recommended publications
  • Multistage Analysis of Variants in the Inflammation Pathway and Lung Cancer Risk in Smokers
    Published OnlineFirst May 9, 2012; DOI: 10.1158/1055-9965.EPI-12-0352-T Cancer Epidemiology, Research Article Biomarkers & Prevention Multistage Analysis of Variants in the Inflammation Pathway and Lung Cancer Risk in Smokers Margaret R. Spitz1, Ivan P. Gorlov2, Qiong Dong3, Xifeng Wu3, Wei Chen4, David W. Chang3, Carol J. Etzel3, Neil E. Caporaso5, Yang Zhao8, David C. Christiani8, Paul Brennan9, Demetrius Albanes7, Jianxin Shi6, Michael Thun10, Maria Teresa Landi5, and Christopher I. Amos4 Abstract Background: Tobacco-induced lung cancer is characterized by a deregulated inflammatory microenviron- ment. Variants in multiple genes in inflammation pathways may contribute to risk of lung cancer. Methods: We therefore conducted a three-stage comprehensive pathway analysis (discovery, replication, and meta-analysis) of inflammation gene variants in ever-smoking lung cancer cases and controls. A discovery set (1,096 cases and 727 controls) and an independent and nonoverlapping internal replication set (1,154 cases and 1,137 controls) were derived from an ongoing case–control study. For discovery, we used an iSelect BeadChip to interrogate a comprehensive panel of 11,737 inflammation pathway single-nucleotide poly- morphisms (SNP) and selected nominally significant (P < 0.05) SNPs for internal replication. Results: There were six SNPs that achieved statistical significance (P < 0.05) in the internal replication data set with concordant risk estimates for former smokers and five concordant and replicated SNPs in current smokers. Replicated hits were further tested in a subsequent meta-analysis using external data derived from two published genome-wide association studies (GWAS) and a case–control study. Two of these variants (a BCL2L14 SNP in former smokers and an SNP in IL2RB in current smokers) were further validated.
    [Show full text]
  • Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine
    Published OnlineFirst September 14, 2016; DOI: 10.1158/2159-8290.CD-16-0263 RESEARCH BRIEF Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition Mary T. Scott 1 , 2 , Koorosh Korfi 1 , 2 , Peter Saffrey 1 , Lisa E.M. Hopcroft 2 , Ross Kinstrie 1 , Francesca Pellicano 2 , Carla Guenther 1 , 2 , Paolo Gallipoli 2 , Michelle Cruz 1 , Karen Dunn 2 , Heather G. Jorgensen 2 , Jennifer E. Cassels 2 , Ashley Hamilton 2 , Andrew Crossan 1 , Amy Sinclair 2 , Tessa L. Holyoake 2 , and David Vetrie 1 ABSTRACT A major obstacle to curing chronic myeloid leukemia (CML) is residual disease main- tained by tyrosine kinase inhibitor (TKI)–persistent leukemic stem cells (LSC). These are BCR–ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensi- tizing them to apoptosis upon treatment with an EZH2-specifi c inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused signifi cant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in signifi cant loss of LSCs compared to TKI alone, in vitro , and in long-term bone marrow murine xenografts. Our fi ndings point to a promising epigenetic-based thera- peutic strategy to more effectively target LSCs in patients with CML receiving TKIs. SIGNIFICANCE: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a signifi cant unmet clinical need.
    [Show full text]
  • Download.Cse.Ucsc.Edu/ Early Age of Onset (~2.5 Years) of This PRA Form in Goldenpath/Canfam2/Database/) Using Standard Settings
    Kropatsch et al. Canine Genetics and Epidemiology (2016) 3:7 DOI 10.1186/s40575-016-0037-x RESEARCH Open Access A large deletion in RPGR causes XLPRA in Weimaraner dogs Regina Kropatsch1*, Denis A. Akkad1, Matthias Frank2, Carsten Rosenhagen3, Janine Altmüller4,5, Peter Nürnberg4,6,7, Jörg T. Epplen1,8 and Gabriele Dekomien1 Abstract Background: Progressive retinal atrophy (PRA) belongs to a group of inherited retinal disorders associated with gradual vision impairment due to degeneration of retinal photoreceptors in various dog breeds. PRA is highly heterogeneous, with autosomal dominant, recessive or X-linked modes of inheritance. In this study we used exome sequencing to investigate the molecular genetic basis of a new type of PRA, which occurred spontaneously in a litter of German short-hair Weimaraner dogs. Results: Whole exome sequencing in two PRA-affected Weimaraner dogs identified a large deletion comprising the first four exons of the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene known to be involved in human retinitis pigmentosa and canine PRA. Screening of 16 individuals in the corresponding pedigree of short-hair Weimaraners by qPCR, verified the deletion in hemizygous or heterozygous state in one male and six female dogs, respectively. The mutation was absent in 88 additional unrelated Weimaraners. The deletion was not detectable in the parents of one older female which transmitted the mutation to her offspring, indicating that the RPGR deletion represents a de novo mutation concerning only recent generations of the Weimaraner breed in Germany. Conclusion: Our results demonstrate the value of an existing DNA biobank combined with exome sequencing to identify the underlying genetic cause of a spontaneously occurring inherited disease.
    [Show full text]
  • HAC-1, a Drosophila Homolog of APAF-1 and CED-4, Functions in Developmental and Radiation-Induced Apoptosis
    Molecular Cell, Vol. 4, 745±755, November, 1999, Copyright 1999 by Cell Press HAC-1, a Drosophila Homolog of APAF-1 and CED-4, Functions in Developmental and Radiation-Induced Apoptosis Lei Zhou, Zhiwei Song,² Jan Tittel,² generation of a large (p20) and small (p10) subunit. Cas- and Hermann Steller* pases can be activated through cleavage by active ªiniti- Howard Hughes Medical Institute atorº caspases in a caspase cascade (Li et al., 1997), Department of Biology and by autoproteolysis following aggregation of two or Massachusetts Institute of Technology more zymogen molecules (MacCorkle et al., 1998; Muzio Cambridge, Massachusetts 02139 et al., 1998; Yang et al., 1998). Upon activation of ªexecu- tionerº caspases, a wide variety of specific intracellular proteins are cleaved in different cellular compartments, and it is thought that their breakdown ultimately leads to Summary the characteristic morphological changes of apoptosis (Nicholson and Thornberry, 1997). The activation of cas- We have identified a Drosophila homolog of Apaf-1 pases appears to be tightly controlled by both positive and ced-4, termed hac-1. Like mammalian APAF-1, HAC-1 can activate caspases in a dATP-dependent and negative regulators. On the one hand, members of manner in vitro. During embryonic development, hac-1 the IAP (inhibitor of apoptosis protein) family can inhibit is prominently expressed in regions where cells un- caspases and apoptosis in a variety of insect and verte- dergo natural death. Significantly, hac-1 transcription brate systems (Uren et al., 1998; Deveraux and Reed, is also rapidly induced upon ionizing irradiation, similar 1999). On the other hand, caspase activation is stimu- to the proapoptotic gene reaper.
    [Show full text]
  • Analysis of Trans Esnps Infers Regulatory Network Architecture
    Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Anat Kreimer All rights reserved ABSTRACT Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer eSNPs are genetic variants associated with transcript expression levels. The characteristics of such variants highlight their importance and present a unique opportunity for studying gene regulation. eSNPs affect most genes and their cell type specificity can shed light on different processes that are activated in each cell. They can identify functional variants by connecting SNPs that are implicated in disease to a molecular mechanism. Examining eSNPs that are associated with distal genes can provide insights regarding the inference of regulatory networks but also presents challenges due to the high statistical burden of multiple testing. Such association studies allow: simultaneous investigation of many gene expression phenotypes without assuming any prior knowledge and identification of unknown regulators of gene expression while uncovering directionality. This thesis will focus on such distal eSNPs to map regulatory interactions between different loci and expose the architecture of the regulatory network defined by such interactions. We develop novel computational approaches and apply them to genetics-genomics data in human. We go beyond pairwise interactions to define network motifs, including regulatory modules and bi-fan structures, showing them to be prevalent in real data and exposing distinct attributes of such arrangements. We project eSNP associations onto a protein-protein interaction network to expose topological properties of eSNPs and their targets and highlight different modes of distal regulation.
    [Show full text]
  • Knock-In of a 25-Kilobase Pair BAC-Derived Donor Molecule By
    ManuscriptbioRxiv preprint doi: https://doi.org/10.1101/076612; this version posted SeptemberClick here23, 2016. to download The copyright Manuscript holder for this BIM preprint CRISPR (which Paper.docxwas not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 2 3 4 5 6 7 8 Knock-In of a 25-Kilobase Pair BAC-Derived Donor Molecule 9 by Traditional and CRISPR/Cas9-Stimulated Homologous Recombination 10 11 Short title: 25-Kilobase Pair Traditional and CRISPR/Cas9-Stimulated Knock-Ins 12 13 14 15 16 17 18 19 20 Tiffany Leidy-Davis1, Kai Cheng1,†, Leslie O. Goodwin1, Judith L. Morgan1, Wen Chun Juan2,‡, Xavier Roca3, 21 Sin-Tiong Ong4-7, David E. Bergstrom1,8,* 22 23 24 25 26 27 28 29 30 31 32 33 1Genetic Resource Science, The Jackson Laboratory, Bar Harbor, ME, USA 34 2Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 35 3 School of Biological Sciences, Nanyang Technological University, Singapore 36 4Cancer and Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore 37 5Department of Haematology, Singapore General Hospital, Singapore 38 6Department of Medical Oncology, National Cancer Centre Singapore, Singapore 39 7Department of Medicine, Duke University Medical Center, Durham, NC, USA 40 8Cancer Center, The Jackson Laboratory, Bar Harbor, ME, USA 41 42 43 44 †Current address: Genetically Engineered Models and Services, Charles River Laboratories, Wilmington, MA, 45 USA 46 47 48 49 ‡ Current address: MSD Pharma (Singapore) Private Limited, Singapore 50 51 52 53 *To whom correspondence should be addressed at [email protected] 54 55 1 bioRxiv preprint doi: https://doi.org/10.1101/076612; this version posted September 23, 2016.
    [Show full text]
  • Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration
    The Journal of Neuroscience, March 20, 2013 • 33(12):5195–5207 • 5195 Neurobiology of Disease Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration Katharina E. Cosker,1,2,3 Maria F. Pazyra-Murphy,1,2,3 Sara J. Fenstermacher,1,2,3 and Rosalind A. Segal1,2,3 1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and Departments of 2Cancer Biology and 3Pediatric Oncology, Dana- Farber Cancer Institute, Boston, Massachusetts 02215 Establishment of neuronal circuitry depends on both formation and refinement of neural connections. During this process, target- derived neurotrophins regulate both transcription and translation to enable selective axon survival or elimination. However, it is not known whether retrograde signaling pathways that control transcription are coordinated with neurotrophin-regulated actions that transpire in the axon. Here we report that target-derived neurotrophins coordinate transcription of the antiapoptotic gene bclw with transport of bclw mRNA to the axon, and thereby prevent axonal degeneration in rat and mouse sensory neurons. We show that neurotrophin stimulation of nerve terminals elicits new bclw transcripts that are immediately transported to the axons and translated into protein. Bclw interacts with Bax and suppresses the caspase6 apoptotic cascade that fosters axonal degeneration. The scope of bclw regulation at the levels of transcription, transport, and translation provides a mechanism whereby sustained neurotrophin stimulation
    [Show full text]
  • Synergy of Bcl2 and Histone Deacetylase Inhibition Against Leukemic Cells from Cutaneous T-Cell Lymphoma Patients Benoit Cyrenne
    Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine January 2018 Synergy Of Bcl2 And Histone Deacetylase Inhibition Against Leukemic Cells From Cutaneous T-Cell Lymphoma Patients Benoit Cyrenne Follow this and additional works at: https://elischolar.library.yale.edu/ymtdl Recommended Citation Cyrenne, Benoit, "Synergy Of Bcl2 And Histone Deacetylase Inhibition Against Leukemic Cells From Cutaneous T-Cell Lymphoma Patients" (2018). Yale Medicine Thesis Digital Library. 3388. https://elischolar.library.yale.edu/ymtdl/3388 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. i Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the Degree of Doctor of Medicine Benoit M. Cyrenne 2018 ii SYNERGY OF BCL2 AND HISTONE DEACETYLASE INHIBITION AGAINST LEUKEMIC CELLS FROM CUTANEOUS T-CELL LYMPHOMA PATIENTS. Benoit Cyrenne, Julia Lewis, Jason Weed, Kacie Carlson, Fatima Mirza, Francine Foss, and Michael Girardi. Department of Dermatology, Yale University, School of Medicine, New Haven, CT. The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted.
    [Show full text]
  • HDAC Inhibition Activates the Apoptosome Via Apaf1 Upregulation
    Buurman et al. Eur J Med Res (2016) 21:26 DOI 10.1186/s40001-016-0217-x European Journal of Medical Research RESEARCH Open Access HDAC inhibition activates the apoptosome via Apaf1 upregulation in hepatocellular carcinoma Reena Buurman, Maria Sandbothe, Brigitte Schlegelberger and Britta Skawran* Abstract Background: Histone deacetylation, a common hallmark in malignant tumors, strongly alters the transcription of genes involved in the control of proliferation, cell survival, differentiation and genetic stability. We have previously shown that HDAC1, HDAC2, and HDAC3 (HDAC1–3) genes encoding histone deacetylases 1–3 are upregulated in primary human hepatocellular carcinoma (HCC). The aim of this study was to characterize the functional effects of HDAC1–3 downregulation and to identify functionally important target genes of histone deacetylation in HCC. Methods: Therefore, HCC cell lines were treated with the histone deacetylase inhibitor (HDACi) trichostatin A and by siRNA-knockdown of HDAC1–3. Differentially expressed mRNAs were identified after siRNA-knockdown of HDAC1–3 using mRNA expression profiling. Findings were validated after siRNA-mediated silencing of HDAC1–3 using qRTPCR and Western blotting assays. Results: mRNA profiling identified apoptotic protease-activating factor 1 (Apaf1) to be significantly upregulated after HDAC inhibition (HLE siRNA#1/siRNA#2 p < 0.05, HLF siRNA#1/siRNA#2 p < 0.05). As a component of the apoptosome, a caspase-activating complex, Apaf1 plays a central role in the mitochondrial caspase activation pathway of apopto- sis. Using annexin V, a significant increase in apoptosis could also be shown in HLE (siRNA #1 p 0.0034) and HLF after siRNA against HDAC1–3 (Fig.
    [Show full text]
  • BCL2L10 Antibody
    Efficient Professional Protein and Antibody Platforms BCL2L10 Antibody Basic information: Catalog No.: UMA21342 Source: Mouse Size: 50ul/100ul Clonality: Monoclonal 8A11G12 Concentration: 1mg/ml Isotype: Mouse IgG2a Purification: The antibody was purified by immunogen affinity chromatography. Useful Information: WB:1:500 - 1:2000 Applications: FCM:1:200 - 1:400 ELISA:1:10000 Reactivity: Human Specificity: This antibody recognizes BCL2L10 protein. Purified recombinant fragment of human BCL2L10 (AA: 31-186) expressed Immunogen: in E. Coli. The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activi- ties. The protein encoded by this gene contains conserved BH4, BH1 and BH2 domains. This protein can interact with other members of BCL-2 pro- tein family including BCL2, BCL2L1/BCL-X(L), and BAX. Overexpression of Description: this gene has been shown to suppress cell apoptosis possibly through the prevention of cytochrome C release from the mitochondria, and thus acti- vating caspase-3 activation. The mouse counterpart of this protein is found to interact with Apaf1 and forms a protein complex with Caspase 9, which suggests the involvement of this protein in APAF1 and CASPASE 9 related apoptotic pathway. Uniprot: Q9HD36 BiowMW: 22kDa Buffer: Purified antibody in PBS with 0.05% sodium azide Storage: Store at 4°C short term and -20°C long term. Avoid freeze-thaw cycles. Note: For research use only, not for use in diagnostic procedure. Data: Gene Universal Technology Co. Ltd www.universalbiol.com Tel: 0550-3121009 E-mail: [email protected] Efficient Professional Protein and Antibody Platforms Figure 1:Black line: Control Antigen (100 ng);Purple line: Antigen (10ng); Blue line: Antigen (50 ng); Red line:Antigen (100 ng) Figure 2:Western blot analysis using BCL2L10 mAb against human BCL2L10 (AA: 31-186) re- combinant protein.
    [Show full text]
  • Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives
    cancers Review Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives Shirin Hafezi 1 and Mohamed Rahmani 1,2,* 1 Research Institute of Medical & Health Sciences, University of Sharjah, P.O. Box 27272 Sharjah, United Arab Emirates; [email protected] 2 Department of Basic Medical Sciences, College of Medicine, University of Sharjah, P.O. Box 27272 Sharjah, United Arab Emirates * Correspondence: [email protected]; Tel.: +971-6505-7759 Simple Summary: Apoptosis, a programmed form of cell death, represents the main mechanism by which cells die. Such phenomenon is highly regulated by the BCL-2 family of proteins, which includes both pro-apoptotic and pro-survival proteins. The decision whether cells live or die is tightly controlled by a balance between these two classes of proteins. Notably, the pro-survival Bcl-2 proteins are frequently overexpressed in cancer cells dysregulating this balance in favor of survival and also rendering cells more resistant to therapeutic interventions. In this review, we outlined the most important steps in the development of targeting the BCL-2 survival proteins, which laid the ground for the discovery and the development of the selective BCL-2 inhibitor venetoclax as a therapeutic drug in hematological malignancies. The limitations and future directions are also discussed. Abstract: The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins Citation: Hafezi, S.; Rahmani, M.
    [Show full text]
  • The Nature of Programmed Cell Death
    Biological Theory https://doi.org/10.1007/s13752-018-0311-0 ORIGINAL ARTICLE The Nature of Programmed Cell Death Pierre M. Durand1 · Grant Ramsey2 Received: 14 March 2018 / Accepted: 10 October 2018 © Konrad Lorenz Institute for Evolution and Cognition Research 2018 Abstract In multicellular organisms, cells are frequently programmed to die. This makes good sense: cells that fail to, or are no longer playing important roles are eliminated. From the cell’s perspective, this also makes sense, since somatic cells in multicel- lular organisms require the cooperation of clonal relatives. In unicellular organisms, however, programmed cell death (PCD) poses a difficult and unresolved evolutionary problem. The empirical evidence for PCD in diverse microbial taxa has spurred debates about what precisely PCD means in the case of unicellular organisms (how it should be defined). In this article, we survey the concepts of PCD in the literature and the selective pressures associated with its evolution. We show that defini- tions of PCD have been almost entirely mechanistic and fail to separate questions concerning what PCD fundamentally is from questions about the kinds of mechanisms that realize PCD. We conclude that an evolutionary definition is best able to distinguish PCD from closely related phenomena. Specifically, we define “true” PCD as an adaptation for death triggered by abiotic or biotic environmental stresses. True PCD is thus not only an evolutionary product but must also have been a target of selection. Apparent PCD resulting from pleiotropy, genetic drift, or trade-offs is not true PCD. We call this “ersatz PCD.” Keywords Adaptation · Aging · Apoptosis · Price equation · Programmed cell death · Selection · Unicellular organisms Introduction in animal ontogeny, was made explicit several decades later (Glücksmann 1951; Lockshin and Williams 1964).
    [Show full text]