Apoptosis: Programmed cell death at a molecular level*,*,**
Section snippets
The extrinsic pathway
Activation of apoptotic pathways and programmed cell death are initiated by the binding of a specific protein ligand to a cell surface transmembrane receptor (Fig 1).
The Bcl-2 family: Pro- and antiapoptotic proteins
Human bcl-2 was the first protooncogene identified to function by protecting cells from programmed cell death (50, 51, 52, 53, 54, 55). It was recognized early that Bcl-2 was a mammalian homologue of the antideath protein cell death abnormal (ced)-9 of the nematode C elegans, and was mainly located on the outer membrane of mitochondria, but was also on the endoplasmic reticular membrane and outer nuclear envelope (50, 51, 52, 53, 54, 55). Mutations of ced-9 that decreased or eliminated its
Regulation of apoptosis by transcription factor NF-κB
NF-κB is a collective term that refers to a family of proteins involved in inflammatory reactions, lymphoid organ development, and innate and adaptive immunity. For purposes of this review, the action of NF-κB in pro- and antiapoptotic cellular responses is the focus. NF-κBs are dimeric transcription factors in the Rel family that are regulated by shuttling within cells from the cytoplasm to the nucleus in response to various stimuli (90). Maintained as an inactive form in the cytoplasm, on
Methods for detection of apoptotic cell death
Table 2 tabulates, briefly describes, and references some of the more commonly used methods to detect apoptotic cell death.Method* Description Distinguishes Apoptosis From Necrosis Reference Gel electrophoresis to detect DNA fragmentation in apoptotic cells† DNA ladders (200-5000 bp fragments): visualized after staining gels with fluorescent or chromogenic reagents Yes 98-100 TUNEL methods In situ—end labeling of free 3′ ends of DNA fragments by
Recognition and removal of apoptotic cells
Of the phospholipids distributed in membranes of viable cells, anionic phosphatidylserine is totally located in the inner leaflet (cytoplasmic side), and is not normally in contact with blood components. After the death pathways described previously have been activated in these cells, a specific sequence of highly regulated events takes place in which phosphatidylserine is translocated from the inner to the outer leaflet of the plasma membrane (ie, the cell surface) and is exposed to the
Regulation of apoptosis by viruses
Many viruses have evolved molecules that regulate apoptosis in cells of the host. For example, crmA is expressed by the cowpox virus, and is an antiapoptotic protein that potently blocks Fas- and TNF-induced apoptosis by inhibiting caspase activation (194). The inhibitory action by the cowpox factor prolongs replication in host cells. Another protein (p35) encoded by baculoviruses also inhibits caspases (195). The IAP family of proteins, of which there are several cellular homologues, blocks
References (221)
- et al.
Apoptosis genes and autoimmunity
Curr Opin Immunol
(2000) - et al.
Caspases: more than just killers?
Trends Immunol
(2001) - et al.
A novel domain within the 55 kd TNF receptor signals cell death
Cell
(1993) - et al.
Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family
Cell
(1993) - et al.
Regulated commitment of TNF receptor signaling: a molecular switch for death or activation
Immunity
(1999) - et al.
FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis
J Biol Chem
(1996) - et al.
FLICE, a novel FADD-homologous ICE/CED-3-like signaling protease, is recruited to the CD95 (FAS/APO-1) death-inducing complex
Cell
(1996) - et al.
Mutational analysis and NMR studies of the death domain of the tumor necrosis factor receptor-1
J Mol Biol
(2000) Apoptosis and the dilemma of cancer chemotherapy
Blood
(1997)- et al.
The role of c-FLIP in modulation of CD95-induced apoptosis
J Biol Chem
(1999)
Modulation of caspase-8 and FLICE-inhibitor inhibitor protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt's lymphoma
Blood
Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis
Cell
Ceramide induces cytochrome c release from isolated mitochondria
J Biol Chem
Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c
Cell
Cytochrome c and dATP-dependent formation of Apaf-1/caspase 9 complex initiates an apoptotic protease cascade
Cell
Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation
Cell
Escaping cell death: survival proteins in cancer
Exp Cell Res
Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival
Blood
A1 is a constitutive and inducible Bcl-2 homologue in mature human neutrophils
Biochem Biophys Res Commun
Cytochrome c and dATP-dependent formation of Apaf-1/caspase 9 complex initiates an apoptotic protease cascade
Cell
Mitochondrial control of apoptosis: the role of cytochrome c
Biochim Biophys Acta
The Bcl-2 protein family
Exp Cell Res
Bcl-2 family proteins: the role of the BH3 domain in apoptosis
Trends Cell Biol
New members of the Bcl-2 family and their protein partners
Curr Opin Genet Dev
Solution structure of the pro-apoptotic molecule Bid: A structural basis for apoptotic agonists and antagonists
Cell
Molecular thanatopsis: a discourse on the BCL2 family and cell death
Blood
Bcl-2 family: life or death switch
FEBS Lett
Missing pieces in the NF-κB puzzle
Cell
Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics
Br J Cancer
Regulation of synoviocytes proliferation, apoptosis, and invasion by the p53 tumor suppressor gene
Am J Pathol
Fas/Fas ligand deficiency results in altered localization of anti-double-stranded DNA B cells and dendritic cells
J Immunol
Killers or clean-up crew. How central are the central mechanisms of apoptosis
Dendritic cells and the control of immunity
Nature
Dendritic cells as sensors of infection
Immunity
Fas ligand-induced apoptosis as a mechanism of immune privilege
Science
A role for CD95 ligand in preventing graft rejection
Nature
Not so Fas: re-evaluating the mechanisms of immune privilege and tumor escape
Nature Med
Death receptors: signaling and modulation
Science
Calpain activation is upstream of caspases in radiation-induced apoptosis
Cell Death Differ
Cathepsin B contributes to TNF-α-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c
J Clin Invest
Noncaspase proteases in apoptosis
Leukemia
The enigma of cell death in neurodenerative disorders
J Neural Transm
TNF-induced signaling in apoptosis
J Clin Immunol
Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors
Science
The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis
Cell
Expression of the functional soluble form of human fas ligand in activated lymphocytes
EMBO J
Tumor necrosis factor receptor and Fas signaling mechanisms
Annu Rev Immunol
FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis
Science
Death ligand TRAIL induces no apoptosis but inhibits activation of human (auto) antigen-specific T cells
J Immunol
A caspase-activated DNAase that degrades DNA during apoptosis, and its inhibitor ICAD
Nature
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Duane R. Schultz, PhD: Professor of Medicine, Division of Rheumatology & Immunology, Department of Medicine, University of Miami School of Medicine, Miami, FL; William J. Harrington, Jr., MD: Professor of Medicine, Division of Hematology/Oncology, Department of Medicine, University of Miami School of Medicine, Miami, FL.
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Address reprint requests to Duane R. Schultz, PhD, Division of Rheumatology & Immunology (R-102), Department of Medicine, University of Miami School of Medicine, PO Box 016960, Miami, FL 33101.
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