Apoptosis Signal Transduction Pathways Research Articles

A novel Bcl-2 small molecule inhibitor 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB)-induced apoptosis in leukemia cells

A novel small molecule inhibitor, 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB), competes with the Bak BH3 peptide to bind Bcl-2 protein with a binding affinity of IC(50) = 0.70 microM, as assessed by a fluorescence polarization based binding assay. HL-60 cells express the highest levels of Bcl-2 among the cell lines examined. Treated with 5 microM of MNB only for 6 h, 85% of HL-60 cells were detected to undergo apoptosis. Pan-caspase inhibitor, Z-VAD-FMK, blocks MNB-induced apoptosis in HL-60 cells. Caspase-2, caspase-3, caspase-7, caspase-8, caspase-9, and PARP activation were observed at as early as 4 to 6 h of MNB treatment. In addition, it has been confirmed that the caspase-3 specific inhibitor, Z-DEVD-FMK, blocks the activation of caspase-8 in MNB-treated HL-60 cells. MNB treatment does not change Bcl-2 or Bax expression level in HL-60 cells, but causes Bid cleavage. Further experiments have illustrated that MNB inhibits the heterodimerization of Bcl-2 with Bax or Bid, reduces the mitochondrial membrane potential (DeltaPsimt), and induces cytochrome c release from mitochondria in HL-60 cells. These results suggest that MNB induces apoptosis in HL-60 by inhibiting the heterodimerization of Bcl-2 with pro-apoptosis Bcl-2 members, resulting in a decrease in the mitochondrial membrane potential and cytochrome c release, activation of caspases and PARP; it is a caspase-dependent process in which the activation of caspase-8 is dependent on the mitochondrial apoptosis signal transduction pathway. MNB prolongs the life spans of HL-60 bearing mice, potently kills fresh AML and ALL cells, indicating that it has the potential to be developed to treat leukemia.

Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy

Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, gamma-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.

Transient elevation of intracellular calcium ion levels as an early event in T-2 toxin-induced apoptosis in human promyelotic cell line HL-60.

Recently we have reported that T-2 toxin, a trichothecene mycotoxin produced by Fusarium species, is a potent inducer of apoptosis in the human promyelotic cell line HL-60. To clarify the signal transduction pathway of apoptosis primed by T-2 toxin, T-2 toxin-induced apoptosis was investigated in detail using confocal laser microscopy and flow cytometry. Apoptosis in HL-60 cells induced by T-2 toxin was dose dependent when the cells were treated with concentrations of 5-100 ng/ml for more than 2 hr. The apoptosis proceeds through various cell cycle stages of HL-60 cells. Prior to apoptosis, the intracellular calcium ion (Ca+2i) level was markedly elevated within 3-5 min after exposure to T-2 toxin and returned to normal level thereafter. A well-known chelator for Ca+2i, ethylene-N,N,N', N'-tetraacetic acid 4K acetoxymethyl ester (BAPTA-AM), a Ca+2-dependent endonuclease inhibitor ZnCl2, and calpain inhibitor 1 sharply blocked T-2 toxin-induced apoptosis. These results strongly suggest that the Ca+2 signal triggered by T-2 toxin is transduced by the activation of endonuclease and protease, and ultimately evokes apoptosis.

A possible role of Fas antigen in ejaculated spermatozoa of fertile bulls: an immunocytochemical quantitative approach

The Fas/Fas L system is a widely recognized apoptosis signal transduction pathway in which transmembrane receptor protein (Fas) triggers a programmed cell death when bound by the Fas ligand (Fas L). This system in the testis is believed to be a paracrine signaling system by which Sertoli cells expressing Fas L can initiate killing of Fas-expressing germ cells during spermatogenesis. So far, the presence of Fas antigen in ejaculated spermatozoa was related only to subfertility or infertility conditions. We demonstrated for the first time that normal ejaculated spermatozoa also express Fas antigen. Our data showed that a large percentage of normal ejaculated spermatozoa of fertile bulls are immunocytochemically positive for Fas. Our observations provide further evidence of the "regionalization" of sperm membrane antigens. Furthermore, we suggest that in mature fertile ejaculated spermatozoa the Fas antigen may also provide resistance to programmed cell death, like in some other cells expressing molecules that inhibit the signals induced by Fas or the death program itself. In addition, we suggest that Fas antigen can partly protect the spermatozoa against apoptosis induced by lipoperoxidative damage that can occur spontaneously in the male gamete at various stages in its lifetime.

Effects of Protein Tyrosine Kinase, Protein Tyrosine Phosphatase and Protein Kinase C on the Apoptotic Process of Leukemia Cells and Human Cortex Neurons Managed by Arsenic Trioxide.

Objective Study on the effects of protein tyrosine kinase, protein tyrosine phosphatase and protein kinase C (PKC)on apoptotic process, observe the changes of cytosolic calcium ([Ca2+]i) of human leukemia cells and cortex neurons after clinical relevant dosage of arsenic trioxide (As2O3) exposure in vitro.Methods Marked [Ca2+]I of human leukemia cells and cortex neurons with Fluo-3/AM, assayed the changes of [Ca2+]I with laser confocal microscopy in real-time after managed with As2O3 in different concentrations respectively, detected the effects of protein tyrosine kinase, the protein tyrosine phosphatase and the activation of protein kinase C on these changes with confocal microscopy and Phosphorus radioisotope assay. Assayed the DNA ladders of leukemia cells and cortex neurons after exposed in As2O3.Results As2O3 1μmol/L can increase the [Ca2+]I of NB4 cells remarkably but show no effects on neurons. Vanadate, a kind of protein tyrosine phosphatase inhibitor, can dose-dependently promote the increasing of [Ca2+]I caused by 2, 5, 10μmol/L As2O3.The mean value of total increased rate in 280 seconds after exposed in As2O3 in different concentrations were: 6.5±2.3%, 21.7±2.1 %,49.2±2.5% in NB4 cells, and 6.7±2.1%, 19.4±2.5 %, 52.3±2.7% in cortex neurons respectively. Genistein, a kind of protein tyrosine kinase inhibitor, can dose-dependently decrease the raising of [Ca2+]I caused by 2, 5, 10μmol/L As2O3.The mean value of total inhibited rate in 280 seconds after As2O3 management in different concentrations were 6.7±2.9%, 25.6±2.5 %, 52.2±3.5% in NB4 cells, and 7.8±3.1%, 18.1±2.8%, 51.3±3.3% in cortex neurons respectively. The activation of PKC began when exposed in As2O31μmol/L for 3 h, and keep raising continuously in NB4 cells., DNA ladders appeared after exposed in As2O31μmol/L for 24h. However, no appearances above were found in human cortex neurons. In 2μmol/L As2O3 exposedness, The activation of PKC and DNA ladders appeared in neurons.Conclusions The phosphorylation and dephosphorylation of protein tyrosine kinase and protein tyrosine phosphatase participated in nonspecific apoptosis signal transduction pathway of As2O3, and accompanied with PKC activation. The [Ca2+] elevation was closely related to PKC increasing activation. The tolerances between leukemia cell and cortex neuron to As2O3 were differ in dosage.

The Roles of Apoptosis in Wound Healing and Pulmonary Fibrosis

Apoptosis has fundamental significance in both normal tissue homeostasis and pathophysiological processes such as wound healing, inflammation, and fibrosis. Failure to clear unwanted cells by apoptosis will prolong inflammation due to the release of their toxic contents. In contrast, excessive apoptosis may cause diseases. Examination of lung biopsies from patients with idiopathic pulmonary fibrosis and animal models of lung fibrosis have found apoptotic cells associated with fibrotic lesions. Transforming growth factor-β1 (TGF-β1) has important roles in lung fibrosis and has the potential to induce apoptosis of lung epithelial cells in vitro and in vivo . Administration of TGF-β1 could enhance Fasmediated epithelial cell apoptosis and lung injury via caspase-3 activation, and caspase inhibitors can prevent the development of fibrosis. Recent progress in understanding the mechanisms of lung fibrosis and regulation of apoptosis in various cell types in lung tissue leads us to expect that inhibitors of apoptosis can prevent subsequent increases in collagen levels and may also be useful as novel therapeutic agents in controlling undesirable fibrosis. In this review, the role of apoptosis in the pathogenesis and resolution of fibrotic lesions will be summarized and highlighted, with more detailed discussion on regulation and signal transduction pathway of apoptosis in lung fibrosis. Keywords: lung fibrosis, inflammation, cytokine, apoptosis

Model validation of biological pathways using Petri nets—demonstrated for apoptosis

This paper demonstrates the first steps of a new integrating methodology to develop and analyse models of biological pathways in a systematic manner using well established Petri net technologies. The whole approach comprises step-wise modelling, animation, model validation as well as qualitative and quantitative analysis for behaviour prediction. In this paper, the first phase is addressed how to develop and validate a qualitative model, which might be extended afterwards to a quantitative model. The example used in this paper is devoted to apoptosis, the genetically programmed cell death. Apoptosis is an essential part of normal physiology for most metazoan species. Disturbances in the apoptotic process could lead to several diseases. The signal transduction pathway of apoptosis includes highly complex mechanisms to control and execute programmed cell death. This paper explains how to model and validate this pathway using qualitative Petri nets. The results provide a mathematically unique and valid model enabling the confirmation of known properties as well as new insights in this pathway.

Characterization of apoptosis signal transduction pathways in HL-5 cardiomyocytes exposed to ischemia/reperfusion oxidative stress model.

During ischemia/reperfusion (I/R), cardiomyocytes are exposed to sudden lack of nutrients and successively to radical oxygen species (ROS). In the present study, we used the HL-5 cardiac atrial myocyte cell line exposed to serum/glucose depletion added or not in H(2)O(2) to mimic ROS during ischemia, then replaced in their standard culture medium to simulate reperfusion. We investigated the effects of serum/glucose depletion combined or not to ROS exposure on AKT and MAP kinases activation to address the role of each event with respect to apoptosis. We demonstrate that serum/glucose depletion per se did not induce apoptosis when compared to ROS exposure. In particular, ROS recruited p38MAPK and JNK pathways. SB202190 preventing p38MAPK activity, partially protected HL-5 from apoptosis while blocking JNK, thanks to JNKI, further enhanced apoptosis. Blocking phosphatidylinositol (PI) 3-kinase with LY294002 or ERKs with U0126 was without consequence on apoptosis. Finally, BCL-2 and BCL-X(L/S) expression levels were analyzed in cells exposed to 1 h ischemia followed by 12-h reperfusion in the presence or not of SB202190; BCL-2, but not BCL-X(L/S), expression was decreased in ROS treated cells but SB202190 failed to restore BCL-2 level. Our data suggest that p38MAPK activation primarily mediates ROS-induced apoptosis while concomitant JNK activation would represent a scavenger pathway for cells trying to escape apoptosis.

Dysregulation of Apoptosis and a Novel Mechanism of Defective Apoptotic Signal Transduction in Human B-cell Neoplasms

Apoptotic cell death is essential for normal B-cell development and for shaping the B-cell repertoire. Dysregulation of the Bcl-2 related proteins and alterations of the p53/pl4ARF pathway are implicated in the pathogenesis and treatment resistance in human B-cell malignancies. We found a novel mechanism of dysregulated apoptosis in human B lymphoma Raji cells that differs from that of altered Bcl-2 and p53 functions. This cell line was resistant to nuclear apoptosis induced by various stimuli, and neither mitochondrial activation nor activation of caspase-3 led to DNA fragmentation. DNA in purified Raji nuclei was degraded in the presence of lysates from the apoptosis-sensitive cell line HL-60, whereas Raji cell lysates did not induce DNA fragmentation in HL-60 nuclei. Cleavage of ICAD/DFF-45 was normal. These results indicate that the apoptosis signal transduction pathway is defective downstream of caspase-3 in Raji cell cytoplasm. Therefore, exploring the molecular mechanism in this system should provide insight into apoptosis resistance in human B-cell malignancies.

Protection of T cells from radiation-induced apoptosis by Cepharanthin®

Cepharanthin® (CE) is a medicine that contains several biscoclaurine alkaloids. We examined the effects of CE on radiation-induced T cell apoptosis. Radiation induced apoptosis on T cells in a dose-dependent manner, while CE inhibited radiation-induced apoptosis. CE also attenuated the cytotoxic effects of radiation on the proliferative response of T cells. CE inhibited not only the loss of mitochondrial transmembrane potential but also the activation of caspase 3 in irradiated T cells. Radiation plus CE induced the up-regulation of Bax and the down-regulation of Bcl-2 in T cells in comparison with radiation alone. These results suggest that CE inhibits the signal transduction pathway of apoptosis induced by radiation, regardless of the expression of Bcl-2 or Bax.

Signal transduction pathways of apoptosis and inflammation induced by the tumor necrosis factor receptor family.

Apoptosis has been implicated as a physiologic cell death program critical for homeostasis. Dysregulation of apoptosis may be involved in human diseases such as cancer, AIDS, degenerative and autoimmune diseases, and infectious diseases. Apoptosis may also play important roles in lung diseases in two different ways. First, failure to clear unwanted cells by apoptosis will prolong the inflammation because of the release of their toxic contents. Repair after an acute lung injury requires the elimination of proliferating mesenchymal and inflammatory cells from the alveolar air space or alveolar wall (1). Second, excessive apoptosis may cause disease. An intratracheal injection of agonistic anti-Fas antibody into adult mice causes epithelial cell apoptosis and lung inflammation, which subsequently leads to pulmonary fibrosis (2). DNA damage and apoptosis in lung epithelial cells have been reported in acute lung injury (3), diffuse alveolar damage (4), and idiopathic pulmonary fibrosis (IPF) (5). Therefore, epithelial cell injury is the common manifestation of lung injury, and apoptosis contributes to such injury of epithelial cells. Tumor necrosis factor (TNF)a is a proinflammatory cytokine, which can induce a broad spectrum of biologic effects and is associated with inflammatory lung disease. TNF causes inflammation by damaging tissues and by inducing the expression of adhesion molecules and cytokines in epithelial and endothelial cells, as well as in inflammatory cells. The cellular effects of TNF are mediated by two distinct cell surface receptors termed TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (6). Most cytotoxic effects of TNF are mediated by TNFR1 through interaction of its death domain with the TNFR-associated death domain protein (TRADD) (7). TRADD interacts with Fas-associated death domain protein (FADD) (8) to activate caspase-8, thereby initiating the apoptosis pathway. Death domain is the sequence in TNFR1, TRADD, and FADD. The death domain is a protein–protein interaction domain, and adopter molecules FADD and TRADD use these domains to interact with other death domain– containing molecules and trigger the apoptosis-signaling pathway. Another well known death receptor, Fas, also transduces apoptosis signal through FADD and shares the same signaling machinery downstream of FADD with TNFR (Figure 1). Since the Fas-mediated apoptosis-signaling pathway is relatively short and straight compared with that of TNFR, Fas-ligation takes hours to kill target cells, whereas TNF takes a day or more. Furthermore, TNF does not usually kill most type of cells without metabolic inhibitors, which is different from Fas-ligation. Although TNFR mediates apoptotic signal transduction, it can transduce intracellular signals that activate transcription factor nuclear factor k B (NFk B) by proteolytic breakdown of the inhibitor of k B (I k B). TNFR-associated factor-2 (TRAF2) and receptor interacting protein (RIP) (9) indirectly bind to TNFR1 through TRADD or directly bind to TNFR2 and activate the NFk B–inducing kinase (NIK) (10), which in turn activates the inhibitor of I k B kinase (IKK) complex (11–14). IKK phosphorylates I k B, which leads to I k B degradation and allows NFk B to translocate to the nucleus and activate transcription (Figure 1). TNF or agonistic anti-Fas antibody administration can lead to production of interleukin-8 (IL-8) by colon epithelial cells (15) or by bronchial epithelial cells, in addition to inducing apoptosis in vitro (16). As TNF activates the IL-8 promoter transcriptionally via NFk B activation, IL-8 secretion induced by Fas ligation also seems to be regulated via NFk B activation (16). It has been reported that the kinase activity of NIK is part of the signaling cascade that leads to NFk B activation and that this signaling pathway is common to TNFR and Fas (10). Disruption of the NFk B pathway with the dominant-negative TRAF2 enhances the cytolytic effects of TNF (17). NFk B subunit RelAdeficient (RelA 2 / 2 ) mouse fibroblasts and macrophages with TNF result in a significant reduction in viability, whereas RelA 1 / 1 cells were unaffected (18). Therefore, death receptor activation induces NFk B activation, which triggers inflammation and also plays an important role in regulating apoptosis. Cellular proteins homologous to baculovirus inhibitors of apoptosis (IAPs) block cell death. TRAF1, TRAF2, XIAP, c-IAP1, and c-IAP2 were identified as gene targets of NFk B transcriptional activity (19). The caspases are a family of cystein proteases, and it is now thought that many forms of cell death are ultimately dependent on caspase activation (Figure 1). XIAP, c-IAP1, and c-IAP2 are direct ( Received in original form November 24, 1999 )

The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review.

Microtubules are important cytoskeletal components involved in many cellular events. Antimicrotubule agents including polymerizing agents (paclitaxel and docetaxel) and depolymerizing drugs (vincristine, vinorelbine, and estramustine phosphate) are widely used either alone or in combination with other anticancer drugs. These antimicrotubule agents are promoters of apoptosis in cancer cells. In this review, we discuss the role of bcl-2 family genes in the regulation of apoptosis, and summarize effects of microtubule targeting agents on apoptotic signal transduction pathways. Disruption of microtubule structure by antimicrotubule drugs results in induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein kinases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These protein kinases are associated directly or indirectly with phosphorylation of bcl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to apoptosis. New pathways of antitumor agents could be directed at this p53, p21 and bcl-2/bax function, and may enhance the effect of existing agents.

The aged and stress response

It is generally considered that aged people have less potential for adapting to environmental changes. In this review, an attempt is made to see whether experimental results support the above working hypothesis and how lower adaptation potential is involved in the aging process. Studies with human beings, rats and human diploid fibroblasts showed a gradual reduction of heat shock proteins (HSPs) and their mRNA and DNA binding activity of heat shock factor (HSF) during aging. Furthermore, the activation of HSF from monomer to trimer was reduced irrespective of the presence of comparative amounts of HSF in the aged cells. Cells from elder organisms or late-staged fibroblasts in culture may have altered the redox state and/or abnormal proteins. A clear interpretation of how these changes influence the activation of HSF in aged cells is impossible at present. Stress kinase JNK (Jun NH2kinase) promotes the signal transduction pathway of apoptosis. In contrast, overexpression of HSP suppresses apoptosis mediated by JNK, resulting in the increase of carcinogenic risk of aged cells. HSP as chaperone maintains unfolded intermediate protein to protect aggregation or to form native conformation of nascent protein. On the contrary, this intermediate (rich in beta-sheet) with aid from such as apoprotein E can make insoluble amyloid fibers in the brain of aged people. In certain cases, overexpression of HSP is rather toxic to the cells.

Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1.

Apoptosis signal-regulating kinase (ASK) 1 was recently identified as a mitogen-activated protein (MAP) kinase kinase kinase which activates the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathways and is required for tumor necrosis factor (TNF)-alpha-induced apoptosis; however, the mechanism regulating ASK1 activity is unknown. Through genetic screening for ASK1-binding proteins, thioredoxin (Trx), a reduction/oxidation (redox)-regulatory protein thought to have anti-apoptotic effects, was identified as an interacting partner of ASK1. Trx associated with the N-terminal portion of ASK1 in vitro and in vivo. Expression of Trx inhibited ASK1 kinase activity and the subsequent ASK1-dependent apoptosis. Treatment of cells with N-acetyl-L-cysteine also inhibited serum withdrawal-, TNF-alpha- and hydrogen peroxide-induced activation of ASK1 as well as apoptosis. The interaction between Trx and ASK1 was found to be highly dependent on the redox status of Trx. Moreover, inhibition of Trx resulted in activation of endogenous ASK1 activity, suggesting that Trx is a physiological inhibitor of ASK1. The evidence that Trx is a negative regulator of ASK1 suggests possible mechanisms for redox regulation of the apoptosis signal transduction pathway as well as the effects of antioxidants against cytokine- and stress-induced apoptosis.

Activation of Caspase 3 (CPP32)-Like Proteases Is Essential for TNF-α-Induced Hepatic Parenchymal Cell Apoptosis and Neutrophil-Mediated Necrosis in a Murine Endotoxin Shock Model

AbstractEndotoxin (ET)-induced liver failure is characterized by parenchymal cell apoptosis and inflammation leading to liver cell necrosis. Members of the caspase family have been implicated in the signal transduction pathway of apoptosis. The aim of this study was to characterize ET-induced hepatic caspase activation and apoptosis and to investigate their effect on neutrophil-mediated liver injury. Treatment of C3Heb/FeJ mice with 700 mg/kg galactosamine (Gal) and 100 μg/kg Salmonella abortus equi ET increased caspase 3-like protease activity (Asp-Val-Glu-Asp-substrate) by 1730 ± 140% at 6 h. There was a parallel enhancement of apoptosis (assessed by DNA fragmentation ELISA and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay). In contrast, activity of caspase 1 (IL-1β-converting enzyme)-like proteases (Tyr-Val-Ala-Asp-substrate) did not change throughout the experiment. Caspase 3-like protease activity and apoptosis was not induced by Gal/ET in ET-resistant mice (C3H/HeJ). Furthermore, only murine TNF-α but not IL-1αβ increased caspase activity and apoptosis. Gal/ET caused neutrophil-dependent hepatocellular necrosis at 7 h (area of necrosis, 45 ± 3%). Delayed treatment with the caspase 3-like protease inhibitor Z-Val-Ala-Asp-CH2F (Z-VAD) (10 mg/kg at 3 h) attenuated apoptosis by 81 to 88% and prevented liver cell necrosis (≤5%). Z-VAD had no effect on the initial inflammatory response, including the sequestration of neutrophils in sinusoids. However, Z-VAD prevented neutrophil transmigration and necrosis. Our data indicate that activation of the caspase 3 subfamily of cysteine proteases is critical for the development of parenchymal cell apoptosis. In addition, excessive hepatocellular apoptosis can be an important signal for transmigration of primed neutrophils sequestered in sinusoids.

Advances in apoptosis research.

Apoptosis, also called programmed cell death, has attracted great attention in recent years. After its discovery by Carl Vogt in 1842, apoptosis research was dormant for more than a century. Its rediscovery in the second half of this century, and the coining of the term apoptosis in 1972 by Kerr, Wyllie, and Currie, ignited an unparalleled interest in this field of science. The number of publications related to apoptosis has been growing exponentially every year ever since. This is mainly due to three major advances, two of which have been made recently and one that is currently seen. First, studies with the small nematode Caenorhabditis elegans have identified a number of apoptosis regulating genes--the first evidence that cell death is an active process under genetic control. Many of these genes have mammalian homologs that, like their worm counterparts, seem to regulate mammalian apoptosis. Second, elucidation of the signal transduction pathways of apoptosis has lead especially to the identification of specific death signaling molecules such as a new family of cysteine proteases, the caspases. Third, it has now become clear that many diseases are characterized by dysregulation of apoptotic programs. Many of these programs involve a family of receptors and their ligands, the death receptor/ligand family. The hope now is to interfere with apoptosis regulation in these systems and to develop new therapeutic concepts.

Signal transduction pathways in apoptosis.

Emerging evidence indicates that apoptosis is regulated by some of the same signal transduction pathways previously implicated in other physiological cellular responses, including alterations in intracellular Ca2+ compartmentalization, activation of protein kinases and phosphatases, alteratios in pH and oxidative stress. Interestingly, signals that promote apoptosis in one model can suppress cell death in another, indicating that cellular responses are determined by the intrinsic programming of the cell in question. This review will summarize current knowledge of the signal transduction pathways regulating apoptosis and discuss how they may be coupled to components of the molecular machinery for cell death.