Essential Information & explanations, latest texts & monographs on
Apoptosis.
Apoptosis
Apoptosis is the process of programmed cell death. It is the deliberate suicide of a cell in a multicellular organism for the greater good of the whole individual. In contrast to necrosis, which is a form of cell death that results from acute tissue injury, apoptosis is carried out in an ordered process that generally confers advantages during an organism's life cycle. For example, the differentiation of human fingers requires the cells in between the fingers to initiate apoptosis so that the fingers can separate. As will be explained further on, the way the apoptotic process is executed facilitates the safe disposal of cell corpses and fragments.
The fact that apoptosis has been the subject of increasing attention and research efforts was highlighted by the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner (United Kingdom), H. Robert Horvitz (US) and John E. Sulston (UK) "for their discoveries concerning genetic regulation of organ development and programmed cell death" (see [1] ).
Table of contents showTocToggle("show","hide")
1 Functions of apoptosis
1.1 Cell damage or infection
1.2 Response to stress or DNA damage
1.3 Immune cell regulation
1.4 Development
1.5 Programmed cell death in plant tissue
1.6 Homeostasis
2 Apoptotic process
2.1 Morphology
2.2 Biochemical signals for safe disposal
2.3 Intrinsic and extrinsic inducers
2.4 Biochemical execution
2.5 Apoptosis and the role of interferon in tumor suppression
2.6 Increasing evidence links cancer with defective apoptotic pathways
2.7 Role of apoptotic products in tumor immunity
3 Evolutionary origin of the apoptotic process
4 High-quality free resources on apoptosis
Functions of apoptosis
Cell damage or infection
Apoptosis can occur, for instance, when a cell is damaged beyond repair, or infected with a virus. The "decision" for apoptosis can come from the cell itself, from its surrounding tissue or from a call that is part of the immune system.
If a cell's capability of apoptosis is damaged (for example, by mutation), or if the initiation of apoptosis is blocked (by a virus), a damaged cell can continue dividing without restrictions, developing into cancer. For example, as part of the hijacking of the cell's genetic system carried out by human papiloma viruses (HPV), a gene called E6 is expressed in a product that degrades p53 protein, which is a vital piece of the apoptotic pathway. This severe interference in the apoptotic capability of cells plays a critical role in the fact that persistent infection by oncogenic HPVs can result in the development of cervical cancer (see "Integration of interferon-alpha/beta signaling to p53 responses in tumor suppression and antiviral defense", by Akinori Takaoka et al., Nature Vol. 424, number 6948, July 31, 2003, p. 517).
Response to stress or DNA damage
Stress conditions --such as starvation-- as well as damage to the cell's DNA --resulting from toxicity or exposure to ionizing radiation, such as ultraviolet or X-rays-- can induce a cell to begin an apoptotic process. A fascinating example, resulting from damage to the genome in the cell nucleus, is cell suicide triggered by the nuclear enzyme poli(ADP-ribose) polymerase-1, or PARP-1. This enzyme plays a crucial role in maintaining genomic integrity, and massive activation of PARP-1 can deplete the cell of energy-providing molecules, an event that sends signals from the nucleus for the mitochondrion to start the apoptotic process (see the Perspective "PARP-1 -a Perpetrator of Apoptotic Cell Death?", by Alberto Chiarugi and Michael A. Moskowitz, in Science, Vol. 297, No. 5579, p. 200, and the research report by Seong-Woon Yu, et al., in p. 259, in the same issue).
Immune cell regulation
Some cells of the immune systems, the B cells and T cells, can become autoreactive, attacking healthy body cells. These are destroyed via apoptosis. New T cells are tested for autoimmune reactions within the thymus so that they do not attack healthy body cells right away. About 95% of the freshly produced T cells are killed right away via apoptosis due to autoimmune reactions.
Development
Programmed cell death is an integral part of both plant and metazoa (multicellular animals) tissue development, and it does not elicit the inflammatory response which is characteristic of necrosis (on metazoa, see "Mechanisms and Genes of Cellular Suicide", by Hermann Steller, Science Vol. 267, Mar. 10, 1995, p. 1445; on plants, see references in the section bellow on programmed cell death in plant tissue). In other words, apoptosis does not resemble the sort of reaction that comes as a result of tissue damage due to accident or pathogenic infection. Instead of swelling and bursting --and, hence, spilling their possibly damaging internal contents into extracellular space--, apoptotic cells and their nuclei shrink, and often fragment. In this way, they can be efficiently phagocytosed (and, as a consequence of this, their components reused) by macrophages or by neighboring cells.
Research on chick embryos -- specifically on chick neural tube development -- has suggested how selective cell proliferation, combined with selective apoptosys, sculpts developing tissues in vertebrates. During vertebrate embryo development, structures called the notocord and the floor plate secrete a gradient of the signaling molecule Sonic hedgehog (Shh), and it is this gradient that directs cells to form patterns in the embryonic neural tube: cells that receive Shh in a receptor in their membranes called Patched1 (Ptc1) survive and proliferate; but, in the absence of Shh, one of the ends of this same Ptc1 receptor (the carboxyl-terminal, inside the membrane) is cleaved by caspase-3, an action that exposes an aptotosys-producing domain. (See the Perspective "Longing for Ligand: Hedgehog, Patched, and Cell Death", by Isabel Guerrero and Ariel Ruiz i Altaba, in Science Vol. 301, No. 5634, p. 774; and the research report "Inhibition of Neuroepithelial Patched-Induced Apoptosis by Sonic Hedgehog" by Chantal Thibert, et al., in p. 843 of that same issue, Aug. 8, 2003).
Research like the one carried out by Thibert and her colleagues has begun to clarify some of the fundamental aspects of morphogenesis, or the development of organisms from fertilized eggs to fully-developed animals and plants. It has also suggested specific answers to why normal cells carry out apopotosis when they end up outside the places they should be in body tissues.
Programmed cell death in plant tissue
Although research on programmed cell death (PCD) in plants has not received the sort of attention enjoyed in top scientific journals by its animal counterpart, the role played by PCD in development and sculpturing of vascular plant tissue has not altogether been lost or played down by our "animal kingdom comes first" prejudice. All wikipedians interested in cell biology should be delighted to find "APL regulates vascular tissue identity in Arabidopsis", by Martin Bonke et al., published in Nature Vol. 425, Nov. 13, 2003, p. 181. Even though their article is not specifically focused on PCD, Bonke and coworkers tell us that one of the two long-distance transport systems in vascular plants, xylem, consists of several cell types "the differentiation of which involves deposition of elaborate cell wall thickenings and programmed cell death."
Basic morphological and biochemical features of PCD have been conserved in both plant and animal kingdoms (see Mazal Solomon, et al.: "The Involvement of Cysteine Proteases and Protease Inhibitor Genes in the Regulation of Programmed Cell Death in Plants", The Plant Cell, Vol. 11, 431-444, March 1999. See also related articles in The Plant Cell Online, [2]). It should be noted, however, that specific types of plant cells carry out unique cell death programs. These have common features with animal apoptosis --for instance, nuclear DNA degradation--, but they also have their own peculiarities, such as nuclear degradation being triggered by the collapse of the vacuole in tracheary elements of the xylem. (See Jun Ito and Hiroo Fukuda: "ZEN1 Is a Key Enzyme in the Degradation of Nuclear DNA during Programmed Cell Death of Tracheary Elements", The Plant Cell, Vol. 14, 3201-3211, December 2002.)
Janneke Balk and Christopher J. Leaver, of the Department of Plant Sciences, University of Oxford, carried out research on mutations in the mitochondrial genome of sun-flower cells. Results of this research suggest that mitochondria play the same key role in vascular plant programmed cell death as in other eukaryotic cells (see "The PET1-CMS Mitochondrial Mutation in Sunflower Is Associated with Premature Programmed Cell Death and Cytochrome c Release", The Plant Cell, Vol. 13, 1803-1818, August 2001).
Homeostasis
In the adult organism, the number of cells within an organ or tissue has to be constant within a certain range. Blood and skin cells, for instance, are constantly renewed by their respective progenitor cells; but this proliferation has to be compensated by cell death. This is called homeostasis, although some authors and researchers like Steven Rose and Antonio Damasio have suggested homeodynamics as a more accurate and elocuent term (see Damasio: The Feeling of What Happens, Harcourt Brace & Co., New York, 1999, p. 141).
Homeostasis is achieved when the rate of mitosis (cell proliferation) in the tissue is balanced by cell death. If this equilibrium is disturbed, either of two things happen:
- The cells are dividing faster than they die, effectively developing a tumor.
- The cells are dividing slower than they die, which results in a disorder of cell loss.
Both states can be fatal or highly damaging (see "Apoptosis in the Pathogenesis and Treatment of Desease", by Craig B. Thompson, in Science, Vol. 267, p. 1456, Mar. 10, 1995).
For instance, misregulation of Hedgehog (Hgg) protein signalling (see previous section, Development) has been implicated in several forms of cancer. Hgg, which conveys an anti-apoptotic signal, has been found to be overexpressed in pancreatic adenocarcinoma tissues (see "Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis" by Sarah P. Thayer et al., Nature Vol. 425, pgs. 851-856, Oct. 23, 2003).
Apoptotic process
Morphology
A cell undergoing apoptosis shows a characteristic morphology that can be seen under a microscope:
The cell becomes round (circular). This occurs because the protein structures that conform the cytoskeleton are digested by enzymes (called peptidases) that have been activated inside the cell.
Its nucleus and the DNA inside it undergo condensation.
Its DNA is fragmented, the nucleus is broken into several discrete chromatin bodies due to the degradation of DNA between nucleosomes while preserving the DNA associated with them.
The cell is phagocytosed, or,
The cell breaks apart into several vesicles called apoptotic bodies.
(See the afore-quoted article by Craig B. Thompson, in Science Vol. 267, 1995.)
Biochemical signals for safe disposal
The dying cells that have just been described display "eat me" signals, like phosphatidylserine (PS, a phospholipid from the inner cell-membrane). Phagocytic scavengers, such as macrophages, have specialized receptors that recognize PS and carry out their disposal job in an orderly manner without eliciting an inflammatory response. (See the Perspective "Eat me or die", by Savill et al., in Science, Vol. 302, p. 1516, Nov. 28, 2003, and the corresponding research articles on new work by Li et al., and Wang et al. in the same issue of Science.)
In the studies on mouse embryos lacking PS receptors ("PSR knockout mice")
conducted by Li and colleagues, un-ingested cells undergoing apoptosis accumulated in the brain and lungs, leading to neonatal lethality. These studies show how critical is the role of PS receptor (PSR) in the development of complex organisms such as mammals.
Intrinsic and extrinsic inducers
Apoptotic messages from outside the cell (called extrinsic inducers) will be described in the next section, on biochemical execution of apoptosis.
Apoptotic messages from inside the cell (intrinsic inducers) are a response to stress, such as nutrient deprivation or DNA damage, as explained by Chiarugi and Moskowitz in their previously mentioned article on PARP-1.
Both extrinsic and intrinsic pathways have in common the activation of central effectors of apoptosis, a group of cysteine proteases called caspases, which carry out the cleaving of both structural and functional elements of the cell, resulting in the previously described morphological changes.
Biochemical execution
Caspases are normally suppressed by IAP (inhibitor of apoptosis) proteins (see "Controlling the Caspases", by Stephen W. Fesik and Yigong Shi, in Science, Vol. 294, No. 5546, p. 1477, November 16, 2001). When a cell receives an apoptotic stimulus, IAP activity is relieved after SMAC (Second Mitochondria-derived Activator of Caspases, or its mouse homolog, called DIABLO), a mitochondrial protein, is released into the cytosol. SMAC binds to IAPs, and in doing so "inhibits the inhibitors", effectively preventing them from arresting the apoptotic process.
But before we go on to a short description of how SMAC is released, lets take a look at two well-studied extrinsically induced apoptotic processes: the TNF and the Fas pathways. Keep in mind, however, that both activating and inhibiting factors are present at each step of these pathways.
Tumor necrosis factor (TNF), a 157 amino acid inter-cellular signaling molecule (cytokine) produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. The cell membrane has two specialized receptors for TNF: TNF-R1 and TNF-R2. The binding of TNF to TNF-R1 has been shown to fire-off the pathway that leads to activating the caspases (see "TNF-R1 Signaling: A Beautiful Pathway", by Guoqing Chen and David V. Goeddel, in Science, Vol. 296, No. 5573, p. 1634).
Fas (a.k.a. Apo-1 or CD95), is another receptor of extrinsic apoptotic signals in the cell membrane, and belongs to the TNF receptor superfamily. (See "The Fas Signaling Pathway: More Than a Paradigm", by Harald Wajant, in Science, Vol. 296, No. 5573, p. 1635, May 31, 2002). The Fas ligand (FasL, the protein that binds to Fas and activates the Fas pathway) is a transmembrane protein, and is part of the TNF family. The interaction between Fas and FasL results in the formation of the death-inducing signaling complex (DISC), which contains the Fas-associated death domain protein (FADD) and caspases 8 and 10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis; while in other types of cells (type II), the Fas DISC starts a feed-back loop that spirals into increasing release of pro-apoptotic factors from mitochondria (see bellow), and the amplified activation of caspase-8.
Downstream from TNF-R1 and Fas activation --at least in mammalian cells-- the proapoptotic molecules BAK and BAX are required in order to make the mitchondrial membrane permeable for the release of caspase activators. Just how BAX and BAK are controlled under the normal conditions of cells that are not undergoing apoptosis, is incompletely understood. But it has been found that a mitochondrial outer-membrane protein, VDAC2, interacts with BAK to keep this potentially lethal apoptotic effector under control. When the death signal is received, products of the activation cascade --such as tBID, BIM or BAD-- displace VDAC2: BAK and BAX are activated, and the mitochondrial outer-membrane becomes permeable. This results in the release of caspase activators, including cytochrome c (see "Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells", by Murphy, K.M., et al., in Nature Cell Death and Differentiation, Vol. 7, No. 1, Jan. 2000, p. 102; and "VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis", by Emily H.-Y. Cheng, Tatiana V. Sheiko, et al., in Science, Vol. 301, No. 5632, July 25, 2003, p. 513).
Release of citochrome c and SMAC from the mitochondrion result in the caspase-9 activating apoptosome, which in turn activates executioner caspase-3.
(The canonical Fas pathway is available in Science's Signal Transduction Knowledge Environment, at http://stke.sciencemag.org/cgi/cm/CMP_7966. The canonical TNF pathway is available at http://stke.sciencemag.org/cgi/cm/CMP_7107; but be aware that access to STKE's items is restricted to subscribers.)
The whole process requires energy and a cell machinery not too damaged. If the cell damage is between certain levels, the cell can start the earliest events of apoptosis and then continue with a necrosis.
Readers should be aware, however, that the apoptotic pathways that have been summarily described are subject to regulatory mechanisms, and that there is not a 1-to-1 relationship between the reception of TNF or FasL and the complete execution of an apoptotic pathway. Fas, for instance, has been implicated --in a seemingly ironic way-- in cell proliferation, through pathways that are not yet well understood (see the afore-quoted article by Wajant); and both Fas and TNF-R1 trigger events that activate the transcription factor nuclear factor kappa B, which induces the expression of genes that play an important role in diverse biological processes, including cell growth and death, development, and immune responses (see the afore-quoted paper by Chen and Goeddel).
The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially (but not only) in autoimmune diseases, such as diabetes and multiple sclerosis.
Apoptosis and the role of interferon in tumor suppression
In their previously mentioned article on the "Integration of interferon-alpha/beta signaling to p53 responses...", Takaoka and co-worker describe their research on how interferon alpha and beta (IFN-alpha/beta)induce transcription of the p53 gene, resulting in the increase of p53 protein level and enhancement of cancer cell-apoptosis. p53 is a tumor suppressor, and is considered as a negative-growth and anti-oncogenic factor.
Work carried out by Takaoka and colleagues has contributed to clarify the role played by interferon in the treatment of some forms of human cancer, and has provided knowledge on the link between p53 and IFN alpha/beta. The p53 response not only contributes to tumor suppression, but is also important in eliciting an apoptotic response to viral infection and consequent damage to the cell's reproductive cycle.
Increasing evidence links cancer with defective apoptotic pathways
Liling Yang et al. reported in the Feb. 15, 2003, issue of Cancer Research the results of their work in the role played by a defective death signal in a type of lung cancer cells called NCI-H460 (human non-small cell lung cancer cells). They found that cross-linked inhibitor of apoptosis (XIAP) proteins are overexpressed in H460 cells. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome c (the apoptosome produced by the mitochondrion).
The apoptotic pathway was found to be dramatically restored in H460 cells with a Smac peptide (SmacN7) that targets IAPs. Yang and her team successfully developed a SmacN7 peptide that selectively reversed apoptosis resistance --and, hence, tumor growth-- in H460 cells in mice.
Role of apoptotic products in tumor immunity
An interesting case of re-use and feed-back of apoptotic products was presented by Matthew L. Albert in a research article that won him an Amersham Biosciences & Science Prize for Young Scientists in Molecular Biology, and published in Science Online in December, 2001. Albert described how dendritic Cells, a type of antigen-presenting cells, phagocytose (that is, engulf) apoptotic tumor cells. Upon maturation, these dendritic cells present antigen (derived from the apoptotic corpses) to killer T cells, which are then primed for the eradication of cells undergoing malignant transformation. This apoptosis-dependent pathway for T cell activation is not present during necrosis, and has opened exciting posibilities in tumor immunity research.
Evolutionary origin of the apoptotic process
Biologists had long suspected that mitochondria originated from bacteria that had been incorporated as endosymbionts (that is, a living body "living together inside") of larger, eukaryotic cells. It was Lynn Margulis who, since 1967, began championing this theory, that has since been widely accepted (see "The Birth of Complex Cells", by Christian de Duve, Scientific American Vol. 274, 4, April, 1996). The most convincing evidence for this theory is the fact that mitochondria have their own DNA, and are equipped with their own genes and replication apparatus.
This evolutionary step must have been more than risky for the primitive eukaryotic cells that began to engulf energy-producing bacteria --or, conversely, it must have been a perilous step for the ancestors of mitochondria that began to invade their proto-eukaryotic hosts. The drama is still enacted today in our own white blood cells (which, it must be said, are much better equipped to entrap and destroy bacteria that intend to invade our bodies). Most of the time, invading bacteria are destroyed by the white blood cells; but, oftentimes, the chemical warfare waged by the prokaryotes succeeds, with the known consequences of infection, and the resulting damage.
One of those rare events in evolution, about two billion years before the present, must have made it possible for certain eukaryotes and energy-producing prokaryotes not only to coexist, but to mutually benefit from their symbiosis.
In a very real and immediate sense, it can be said that eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide (see the afore-quoted article by Chiarugi and Moskowitz, in Science 297, p. 200). Given certain signals or insults to cells—such as feed-back from neighbors, stress or DNA damage—mitochondria release caspase activators that produce the cell-death-inducing biochemical cascade.
As has been previously explained at the beginning of this article, however, this fine equilibrium between life and death that all of us eukaryotic beings carry most intimately and deeply, is essential to life.
High-quality free resources on apoptosis
Cancer Medicine, 5th Edition (2000), Robert C. Bast Jr. et al., editors, published by B.C. Decker Inc ([3]).
Entrez is a life sciences information search engine provided by the US National Center for Biotechnology Information ([4]).
Entrez books is a service provided by the NCBI in collaboration with book publishers ([5].
freebooks4doctors promotes free access to medical books ([6])
Molecular biology of the cell, 3th edition (1994), by Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, James D. Watson, published by Garland Publishing, Inc ([7]).
PubMed Central (PMC), provided by the US National Library of Medicine, is a digital archive of life sciences journal literature ([8]).
See also: Immunology -- Biochemistry
The above article is adapted from from Wikipedia All Wikipedia article text is available under the terms of the GNU Free Documentation License
Apoptosis: A Practical Approach (Practical Approach Series (Paper), 216) by George P. Studzinski
When Cells Die II : A Comprehensive Evaluation of Apoptosis and Programmed Cell Death by Richard A. Lockshin
Signalling Pathways in Apoptosis (Modern Genetics) by Dianne Watters
A Means to an End: The Biological Basis of Aging and Death by William R. Clark
Cell Growth and Apoptosis: A Practical Approach (The Practical Approach Series, 159) by George P. Studzinski
Apoptosis and Cancer Chemotherapy (Cancer Drug Discovery and Development, 5) by John A. Hickman
Caspases: Their Role in Cell Death and Cell Survival (Molecular Biology Intelligence Unit, 24) by Marek Los
Mitosis and Apoptosis: Matters of Life and Death by I. D. Bowen
Apoptosis: Techniques and Protocols by Andrea C. Leblanc
When Cells Die: A Comprehensive Evaluation of Apoptosis and Programmed Cell Death by Richard A. Lockshin
Apoptosis: Techniques and Protocols by Judes Poirier
Cell Injury by E. Edward Bittar
Apoptosis Methods in Pharmacology and Toxicology: Approaches to Measurement and Quantification by Myrtle A. Davis
Mechanisms of Cell Death II: The Third Annual Conference of the International Cell Death Society (Annals of the New York Academy of Sciences, V. 926) by Zahra Zakeri
The Neurology of Neuroblastoma: Neuroblastoma As a Neurobiological Disease by Nina Felice Schor
Bibliographic Resources
Updates and comments at Essential Facts blog
Are you interested in Feng Shui?
Price Theory Resources
Fructose, Sucrose, Glucose Core Bibliography
World Class Photographers
Some philosophical movements
Top PDF and eBook Downloads
Recent Apoptosis related patents
From USPTO:
6720425: Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
6720423: Dihydrobenzofuran and dihydrobenzothiophene 2,4-pentadienoic acid derivatives having selective activity for retinoid X (RXR) receptors
6720419: Sulfated fucan oligosaccharide
6720408: MDA-7 nucleic acid molecules and pharmaceutical compositions thereof
6720347: Carbon substituted aminothiazole inhibitors of cyclin dependent kinases
6720346: Thiazole benzamide derivatives and pharmaceutical compositions for inhibiting cell proliferation
6720341: Preventives/remedies for kidney diseases
6720338: N-acylsulfonamide apoptosis promoters
6720332: Oxindole derivatives
6720331: 1-substituted 1,2,3,4-tetrahydro-.beta.-carboline and 3,4-dihydro-.beta.-carboline and analogs as antitumor agents
6720327: Lactone integrin antagonists
6720321: 1,4-disubstituted benzo-fused cycloalkyl urea compounds
6720315: Dihydrostilbene alkanoic acid derivatives
6720311: Polypeptide for the treatment of cancer and a method for preparation thereof
6720182: Alternative splice variants of CD40
6720180: Wounded epithelium-specific transcript
6720162: Assay for kinases and phosphatases
6720158: Splice variants of BRCA1
6719998: Treatment of restenosis
6719987: Antimicrobial bioabsorbable materials
6719978: Virus-like particles for the induction of autoantibodies
6719972: Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA4- specific antibodies
6719969: Treatment of liver disease and injury with CXC chemokines
6719540: C3-cyano epothilone derivatives
6719520: Method and compounds
6717033: Poly ADP-ribose polymerase gene and its uses
6717031: Method for selecting a transgenic mouse model of alzheimer's disease
6716975: Antisense modulation of EDG1 expression
6716968: Apoptosis-related compounds and their use
6716965: Adipocyte complement related protein zacrp13
6716960: Mch3, a novel apoptotic protease, nucleic acids encoding and methods of use
6716870: Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
6716868: (-)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor
6716862: 5-(Substituted)-5-(substitutedsulfonyl or sulfanyl) thiazolidine-2,4-diones useful for inhibition of farnesyl-protein transferase
6716859: Substituted N'-(Arylcarbonyl)-benzhydrazides, N'(Arylcarbonyl)-benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof
6716856: 4,5,6,7-tetrahydroindazole derivatives as antitumor agents
6716851: Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators or caspases and inducers of apoptosis and the use thereof
6716831: 2,4-diamino-pyrimidine deprivatives having anti-cell proliferative activity
6716828: Compounds, methods and pharmaceutical compositions for treating cellular damage, such as neural or cardiovascular tissue damage
6716825: Phosphonate compounds
6716824: Treatment of pancreatic adenocarcinoma by cytotoxic gene therapy
6716822: Therapeutic agent for ischemia which inhibits apoptosis under ischemic condition
6716818: Caspase inhibitors and the use thereof
6716631: Evolution of whole cells and organisms by recursive sequence recombination
6716629: Apparatus for assay, synthesis and storage, and methods of manufacture, use, and manipulation thereof
6716625: Histidine kinases of Aspergillus and other fungal species, related compositions, and methods of use
6716600: Persephin and related growth factors
6716595: Method for detecting sphingosine-1-phosphate (S1P) for cancer detection
6716588: System for cell-based screening
from PUBMED
1: Xiang Y, Sun S, Cai J, Xiang M, Tang G, Cao X.
ENHANCEMENT OF FRACTIONATED BONE MARROW TRANSPLANTATION ON HEMATOPOIETIC CELL
HOMING IN A MOUSE ALLOGENEIC MODEL1.
Transplantation. 2004 Apr 16;77(7):972-978.
PMID: 15087756
2: Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K.
Nuclear translocation of apoptosis-inducing factor after focal cerebral
ischemia.
J Cereb Blood Flow Metab. 2004 Apr;24(4):458-66.
PMID: 15087715
3: Zhou C, Yamaguchi M, Kusaka G, Schonholz C, Nanda A, Zhang JH.
Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog
model of experimental subarachnoid hemorrhage.
J Cereb Blood Flow Metab. 2004 Apr;24(4):419-31.
PMID: 15087711
4: Philips N, Burchill D, O'Donoghue D, Keller T, Gonzalez S.
Identification of benzene metabolites in dermal fibroblasts as nonphenolic:
regulation of cell viability, apoptosis, lipid peroxidation and expression of
matrix metalloproteinase 1 and elastin by benzene metabolites.
Skin Pharmacol Physiol. 2004 May-Jun;17(3):147-52.
PMID: 15087594
5: Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen
X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG,
Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H.
ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease.
Science. 2004 Apr 16;304(5669):448-52.
PMID: 15087549
6: McKay BC, Stubbert LJ, Fowler CC, Smith JM, Cardamore RA, Spronck JC.
Regulation of ultraviolet light-induced gene expression by gene size.
Proc Natl Acad Sci U S A. 2004 Apr 15 [Epub ahead of print]
PMID: 15087501
7: Milutinovic S, Brown SE, Zhuang Q, Szyf M.
DNMT1 knock down induces gene expression by a mechanism independent of the two
epigenetic silencing mechanisms: DNA methylation and histone deacetylation.
J Biol Chem. 2004 Apr 15 [Epub ahead of print]
PMID: 15087453
8: Ondr JK, Pham CT.
Characterization of murine cathepsin W and its role in cell-mediated
cytotoxicity.
J Biol Chem. 2004 Apr 15 [Epub ahead of print]
PMID: 15087452
9: Chen F, Arseven OK, Cryns VL.
Proteolysis of the mismatch repair protein MLH1 by caspase-3 promotes DNA
damage-induced apoptosis.
J Biol Chem. 2004 Apr 15 [Epub ahead of print]
PMID: 15087450
10: Schwarzenbacher R, Stenner-Liewen F, Liewen H, Robinson H, Yuan H,
Bossy-Wetzel E, Reed JC, Liddington RC.
Structure of the Chlamydia protein CADD reveals a redox enzyme that modulates
host-cell apoptosis{
J Biol Chem. 2004 Apr 15 [Epub ahead of print]
PMID: 15087448
11: Reynolds M, Peterson E, Quievryn G, Zhitkovich A.
Human nucleotide excision repair efficiently removes DNA phosphate-chromium
adducts and protects cells against chromate toxicity.
J Biol Chem. 2004 Apr 15 [Epub ahead of print]
PMID: 15087443
12: Shen WH, Zhou JH, Broussard SR, Johnson RW, Dantzer R, Kelley KW.
Tumor Necrosis Factor {alpha} Inhibits Insulin-like Growth Factor-I-Induced
Hematopoietic Cell Survival and Proliferation.
Endocrinology. 2004 Apr 15 [Epub ahead of print]
PMID: 15087433
13: Sasada T, Takedatsu H, Azuma K, Koga M, Maeda Y, Shichijo S, Shoumura H,
Hirai T, Takabayashi A, Itoh K.
Immediate Early Response Gene X-1, a Stress-Inducible Antiapoptotic Gene,
Encodes Cytotoxic T-Lymphocyte (CTL) Epitopes Capable of Inducing Human
Leukocyte Antigen-A33-Restricted and Tumor-Reactive CTLs in Gastric Cancer
Patients.
Cancer Res. 2004 Apr 15;64(8):2882-8.
PMID: 15087407
14: Tai YT, Catley LP, Mitsiades CS, Burger R, Podar K, Shringpaure R,
Hideshima T, Chauhan D, Hamasaki M, Ishitsuka K, Richardson P, Treon SP, Munshi
NC, Anderson KC.
Mechanisms by which SGN-40, a Humanized Anti-CD40 Antibody, Induces
Cytotoxicity in Human Multiple Myeloma Cells: Clinical Implications.
Cancer Res. 2004 Apr 15;64(8):2846-52.
PMID: 15087402
15: Lu B, Mu Y, Cao C, Zeng F, Schneider S, Tan J, Price J, Chen J, Freeman M,
Hallahan DE.
Survivin as a therapeutic target for radiation sensitization in lung cancer.
Cancer Res. 2004 Apr 15;64(8):2840-5.
PMID: 15087401
16: Mo YY, Yu Y, Ee PL, Beck WT.
Overexpression of a dominant-negative mutant Ubc9 is associated with increased
sensitivity to anticancer drugs.
Cancer Res. 2004 Apr 15;64(8):2793-8.
PMID: 15087395
17: Castillo SS, Brognard J, Petukhov PA, Zhang C, Tsurutani J, Granville CA,
Li M, Jung M, West KA, Gills JG, Kozikowski AP, Dennis PA.
Preferential inhibition of Akt and killing of Akt-dependent cancer cells by
rationally designed phosphatidylinositol ether lipid analogues.
Cancer Res. 2004 Apr 15;64(8):2782-92.
PMID: 15087394
18: Sunde M, McGrath KC, Young L, Matthews JM, Chua EL, Mackay JP, Death AK.
TC-1 is a novel tumorigenic and natively disordered protein associated with
thyroid cancer.
Cancer Res. 2004 Apr 15;64(8):2766-73.
PMID: 15087392
19: Ninomiya Y, Kato K, Takahashi A, Ueoka Y, Kamikihara T, Arima T, Matsuda T,
Kato H, Nishida J, Wake N.
K-Ras and H-Ras activation promote distinct consequences on endometrial cell
survival.
Cancer Res. 2004 Apr 15;64(8):2759-65.
PMID: 15087391
20: Hoang BH, Kubo T, Healey JH, Yang R, Nathan SS, Kolb EA, Mazza B, Meyers
PA, Gorlick R.
Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by
modulating the Wnt-beta-catenin pathway.
Cancer Res. 2004 Apr 15;64(8):2734-9.
PMID: 15087387
|