HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McConkey, D. J. Articles by Orrenius, S. Search for Related Content PubMed PubMed Citation Articles by McConkey, D. J. Articles by Orrenius, S.

Signal Transduction Pathways in Apoptosis

^a Department of Cell Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA;
^b Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

Key Words. Apoptosis • Calcium • PKC • cAMP • Ceramide • Cyclin-dependent kinases • Endonuclease • Protease • BCL-2

Dr. David J. McConkey, Department of Cell Biology, Box 173, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

	Abstract

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
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, alterations 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.

	Introduction

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Apoptosis (programmed cell death) is a highly regulated process of selective cell deletion involved in development, normal cell turnover, hormone-induced tissue atrophy, cell-mediated immunity, tumor regression and a growing number of pathological disorders, typified by AIDS and Alzheimer's diseases [1, 2]. The response is characterized by a series of morphological alterations, including plasma and nuclear membrane blebbing, organelle relocalization and compaction, chromatin condensation, and the formation of membrane-enclosed structures termed "apoptotic bodies" that are extruded into the extracellular milieu [2, 3]. Uptake of this cellular debris is carefully controlled; apoptotic cells and bodies are specifically recognized and cleared by neighboring epithelial cells and professional phagocytic cells (macrophages) before their contents can be released into the extracellular milieu, thereby allowing for cell death to occur in the absence of inflammation [3].

The most familiar biochemical feature of apoptosis is endogenous endonuclease activation, resulting in the production of domain-sized large (50-300 kilobase) DNA fragments [4-6] and oligonucleosomal cleavage products commonly referred to as "DNA ladders" [7]. It appears that the smaller fragments are derived from the larger, and it has been suggested that different enzymatic activities are involved in generating each type, as evidenced by their unique cation requirements [8]. More recent work has demonstrated that a family of cysteine proteases homologous to the Caenorhabditis elegans (C. elegans) cell death gene ced-3 and human interleukin 1 (IL-1) converting enzyme (ICE) are also critically involved in the response, as inhibitors of these enzymes block both endonuclease activation and cell death [9-15]. The most familiar of their substrates in apoptotic cells is the 116 kD polypeptide poly (ADP-ribose) polymerase (PARP), which is cleaved at a DEVD site by one or more members of the family to yield an 85 kD fragment [16, 17]. Although ICE itself does not appear to be required for most examples of apoptosis [18], another member of the family that exhibits higher homology to ced-3, termed "apopain" or "CPP32," appears to be more centrally involved [131920]. Precisely how the ICE family regulates endonuclease activation and the other features of apoptosis is not known.

At the molecular level, a family of polypeptides homologous to bcl-2 appears to play particularly important roles in regulating apoptosis. One class of homologs (including bcl-2, bcl-x_L, mcl-1, and several viral proteins) suppresses apoptotic cell death, while another group (bax, bcl-x_s, and bak) promotes apoptosis sensitivity. Korsmeyer's laboratory has provided a possible mechanistic explanation for these differential effects on apoptosis with the observation that the BCL-2 family members form dimers which can apparently impact the process in opposite fashions: BCL-2:BAX heterodimers predominate in cells that are resistant to apoptosis, whereas a preponderance of BAX:BAX homodimers has been linked to susceptibility to cell death [21]. Most importantly, overexpression of BCL-2 or BCL-X_L blocks apoptosis induced by very diverse stimuli, including growth factor withdrawal, tumor necrosis factor (TNF), engagement of the Fas antigen, ionizing radiation, oncogenes such as myc and chemical chemotherapeutic agents [1], strongly suggesting that they function at a downstream site within the apoptotic pathway that is proximal to the effector machinery (proteases and nuclease[s]). Moreover, as is true for the ICE proteases, the apoptosis-regulatory functions of BCL-2 and its homologs are evolutionarily conserved, as the C. elegans cell death suppressor ced-9 is a structural and functional homolog of human bcl-2 [22, 23].

	Regulation by Ca2+

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Several lines of evidence indicate that alterations in the cytosolic Ca²⁺ concentration and/or intracellular Ca²⁺ compartmentalization are involved in the regulation of apoptosis. Treatment of a variety of cell types with the endoplasmic reticular Ca²⁺ ATPase inhibitor thapsigargin or with Ca²⁺ ionophores leads to apoptosis [24-32]. Apoptosis can also be triggered in thymocytes (immature T cells) and primed mature T or B cells by antigen receptor stimulation, responses that are dependent upon sustained Ca²⁺ increases [33]. Glucocorticoid-induced apoptosis in thymocytes and certain T cell lines also involves sustained Ca²⁺ increases that are mediated via Ca²⁺ influx [34]; recent data suggest that these responses are mediated by the type 3 receptor for inositol trisphosphate, a ubiquitous, physiologically relevant Ca²⁺ channel [35]. Furthermore, stimulation of glutamate (NMDA) receptors in neurons leads to Ca²⁺-mediated apoptosis [36], a response that may contribute to excitatory neuronal toxicity. Certain chemical toxins may also promote apoptosis by disrupting intracellular Ca²⁺ homeostasis, leading to nonphysiological Ca²⁺ increases that promote endonuclease activation and apoptotic cell death [37, 38]. Intracellular or extracellular Ca²⁺ chelators, Ca²⁺ channel blockers and calmodulin antagonists can all delay or abolish apoptosis in several model systems. In addition, overexpression of the Ca²⁺-binding protein calbindin D-28K can block apoptotic cell death in lymphocytes [39] and prostate carcinoma cells [32] and can prevent amyotrophic lateral sclerosis (ALS) IgG-mediated cytotoxicity in motoneuron hybrid cells [40]. Finally, recent work suggests that the protective effects of the anti-apoptosis oncoprotein Bcl-2 involve alterations in Ca²⁺ compartmentalization [41-43].

In other cellular systems, however, increases in cytosolic Ca²⁺ block apoptotic cell death. For example, treatment of IL-3-dependent hematopoetic cells with calcium ionophores blocks endogenous endonuclease activation and cell death following withdrawal of IL-3 [44]. In addition, calcium ionophores block apoptosis in aged neutrophils [45], and membrane depolarization, which leads to Ca²⁺ increases in neurons, can prevent apoptosis in response to withdrawal of nerve growth factor in dependent cells [46].

The cellular targets for Ca²⁺ in initiating apoptosis are diverse. Perhaps the most obvious is the endogenous endonuclease itself, which appears to be Ca²⁺-dependent in most (if not all) cell types [33]. Another important effect of elevated Ca²⁺ is transcriptional activation of the genes encoding the surface cell death receptor Fas and its ligand, which participate in an autocrine suicide loop in activated mature T cells. The observation that the immunosuppressants cyclosporine A and FK506 can inhibit Fas and Fas ligand upregulation and prevent cell death in some models [47] strongly suggests that the target of these immunosuppressants, the Ca²⁺/calmodulin-dependent protein phosphatase calcineurin, is involved in these events. Finally, our more recent work has identified a Ca²⁺-dependent nuclear serine protease as another target for Ca²⁺ [48, 49]. This protease cleaves lamin B₁ and histone H1 in thymocytes, CLL lymphocytes, T cell hybridomas, and melanoma cell lines, and inhibitors of the protease can block endonuclease activation, suggesting that the protease directly or indirectly controls endonuclease activation.

	Protein Kinase C

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Much of the evidence for a role for protein kinase C (PKC) activation in apoptosis comes from studies with phorbol esters, a class of tumor promoters that act by binding to the diacylglycerol binding site on the enzyme and promoting its activation. Some studies have demonstrated that phorbol esters stimulate apoptosis in certain cell types [50-52]. It is possible that differential expression and/or activation of particular PKC isoforms is involved, as one study has shown that spontaneous apoptosis in the U-937 human myeloid line is associated with increased PKC-ß and reduced PKC- [53], while another group has shown that overexpression of PKC- in the same cells upregulates PKC- and PKC-ß and sensitizes them to phorbol ester-induced apoptosis [51]. In addition, the selective sensitivity of a multidrug-resistant subclone of the MCF-7 human breast carcinoma to phorbol ester-induced apoptosis is associated with overexpression of PKC- [50]. Furthermore, it has been reported that glucocorticoid-induced apoptosis in thymocytes involves selective activation and translocation of PKC- [54], and circumstantial evidence for a role for PKC- has emerged with the observation that it contains a possible ICE family cleavage site (QDN) and is proteolytically activated in apoptotic U937 cells exposed to ionizing radiation [55].

Other work suggests that PKC activation can also block apoptosis. Phorbol esters and other activators of PKC inhibit endonuclease activation in thymocytes [56], normal [57] and leukemic [58, 59] B cells, a human mammary adenocarcinoma cell line (BT-20) [60], human synovial cells [61], IL-3-dependent hematopoietic cells [62] and kidney epithelial cells [63]. Phorbol esters can also block TNF-mediated apoptosis, presumably due to their effects on the ceramide pathway to apoptosis [60, 64]. Moreover, many PKC antagonists can stimulate apoptosis [65, 66], and the protein kinase inhibitor staurosporine is being used widely as a "universal" trigger of apoptosis [67], although it has not yet been determined whether or not the actions of these inhibitors, which are notoriously nonspecific, require inhibition of PKC.

	cAMP

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Studies of programmed cell death within the secondary palatal epithelium during palatal fusion provided some of the first direct evidence for a role for cyclic adenosine monophosphate (cAMP) in promoting apoptosis [68]. Pharmacological cAMP agonists are also known to be cytotoxic to certain lymphoid lines in vitro [69, 70], and agents that elevate cAMP stimulate DNA fragmentation typical of apoptosis in thymocytes [71, 72]. More recent work has confirmed these observations [73, 74] and extended them to a variety of other model systems, including immortalized primary granulosa cells [75, 76], human mammary carcinoma cells [77] and various normal and transformed T and B cells [78, 79]. As one would predict, cAMP-induced apoptosis involves activation of cAMP-dependent protein kinase (PKA) [71, 80] and specific protein phosphorylation changes [81]. cAMP can also synergize to promote glucocorticoid-induced apoptosis in thymocytes and lymphoid cell lines [82, 83].

However, the effects of cAMP are definitely cell context-dependent, as good evidence has also emerged demonstrating that cAMP can block apoptosis in other model systems. Perhaps the best example can be found in neurons, where cAMP has been shown to inhibit apoptosis in response to ex vivo culture, withdrawal of nerve growth factor, or depletion of extracellular K⁺ [46, 84, 85]. cAMP also prevents spontaneous apoptosis in aged neutrophils [86], in a macrophage cell line exposed to exogenous nitric oxide [87], in ovarian follicles [88] and in T cells activated via the T cell receptor [89-91]. Ongoing work is required to determine if the same molecular targets are involved in the induction and suppression of apoptosis by cAMP.

	Ceramide

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Some receptors stimulate sphingomyelinase and subsequently cause the hydrolysis of sphingomyelin when they bind their ligands, leading to the release of diacylglycerol and ceramide, each of which activates its own protein kinase cascade [92]. A great deal of recent work has demonstrated that ceramide is a fairly common trigger for the apoptosis. A rapid increase in ceramide is observed in TNF-treated fibroblasts, and addition of synthetic ceramide analogs is sufficient to reproduce all of the events observed following TNF treatment [64, 65]. Similar findings have been made in cells exposed to activating anti-Fas antibodies or Fas ligand [93, 94] or ionizing radiation [95]. Furthermore, the cancer chemotherapeutic agent daunorubicin induces ceramide synthesis via a novel mechanism [96]. Evidence has also been advanced that the Reaper cell death-associated polypeptide in Drosophila acts via ceramide production [97], suggesting that its actions may be evolutionarily conserved. However, it is possible that in other cases ceramide acts to suppress cell death, as has been suggested concerning neurons following nerve growth factor withdrawal [98].

Ongoing efforts are aimed at identifying the downstream targets for ceramide in apoptotic cells. Ceramide is known to activate both protein kinase(s) and phosphatase(s) which may both be important for subsequent responses [92], since ceramide-activated protein phosphatase (CAPP) has been implicated in the effects of TNF on HL-60 cells [99], and the stress-activated protein kinase (SAPK)/Jun kinase (JNK) pathway has also been implicated in the effects of TNF in more recent work [100]. The idea that Jun is involved is further supported by the observation that Jun expression is induced by ceramide and that inhibition of Jun expression prevents apoptosis [101]. Activation of Ras may function upstream of these events, as Fas engagement or exposure of cells to ceramide or TNF leads to accumulation of GTP-bound Ras (the active form), and dominant negative forms of Ras prevent Fas-, ceramide- and TNF-induced apoptosis [93, 102]. Ceramide-mediated activation of Ras leads to phosphorylation and activation of Raf1 [103], which may then link Ras to SAPK/JNK and other kinase pathways. Crosstalk between the ceramide pathway and PKC is likely to determine the outcome of ceramide signaling, as phorbol esters and diglycerides are potent inhibitors of ceramide-induced apoptosis [64, 104]. A recent report indicates that the mitogenic ceramide metabolite, sphingosine-1-phosphate, prevents ceramide-mediated apoptosis by the activation of PKC [105]. The retinoblastoma gene product (Rb) may also dictate the cellular response to ceramide, in that it has been reported that ceramide induces dephosphorylation of Rb, thereby promoting its activation and resulting in cell cycle arrest at the G₁ stage [106]. This may prevent apoptosis, as we have shown that overexpression of Rb inhibits ceramide-induced DNA fragmentation in a human bladder carcinoma line (5637) [107].

	Protein Tyrosine Kinases

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Since virtually all surface receptors that promote survival of growth factor-dependent cells regulate cytoplasmic protein tyrosine kinases (PTKs), it could be predicted that PTKs play important roles in suppressing apoptosis. Direct evidence for this has come from the observation that protein tyrosine kinase antagonists can directly induce apoptosis [108] and can inhibit the action of many different survival factors in hematopoietic cells, including IL-2 and IL-3 [109], GM-CSF [110], and stem cell factor [111-114]. Additional examples outside the hematopoietic system include the actions of epidermal growth factor [115, 116] and basic fibroblast growth factor [115] on their target cells in tissues. Finally, a large body of evidence is now available demonstrating that the Abelson (ABL) tyrosine kinase suppresses apoptosis under a variety of circumstances, including growth factor withdrawal [117, 118], Fas engagement [119] and exposure of cells to cancer chemotherapeutics [120, 121]. The latter is likely to be of relevance to the emergence of drug resistance in chronic myelogenous leukemia, where a specific chromosomal translocation leads to fusion of the bcr and abl loci and activation of ABL protein tyrosine kinase function.

Like the other signaling pathways discussed in this review, PTKs have been implicated in promoting apoptosis. Ionizing radiation promotes PTK activation that appears required for apoptosis in B cells [122], and engagement of the Thy-1 [123, 124] or the CD4 or CD8 antigens [125] on CD4⁺CD8⁺ thymocytes promotes T cell receptor-mediated apoptosis via activation of the PTK p56^lck. Similarly, crosslinking CD19 on B cells has been reported to lead to activation of p56^lck and to augment radiation-induced apoptosis in the cells [126].

	Cyclin-Dependent Kinases

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
The growing appreciation of morphological and functional similarities between mitosis and apoptosis has led to an investigation into the potential involvement of the cell cycle kinases in the control of the latter. Molecular evidence for parallel control of the two responses can be found in the observation that Myc [127-129] and p53 [130-132] promote certain apoptotic responses and that both polypeptides are known to regulate cell cycle progression. The first evidence for the involvement of cell cycle-regulating protein kinases and phosphatases in apoptosis came from the observation that apoptosis induced by components of the lytic granules of cytotoxic T lymphocytes (most notably granzyme B/fragmentin) involves "premature" activation of p32/cdc2 [133], a cell cycle kinase that is regulated by cyclins A and B. Independent work by other laboratories has confirmed that a cyclin A-dependent protein kinase(s) is required for apoptosis mediated by Myc [134] and for apoptosis induced in S-phase arrested cells by staurosporine, caffeine, okadaic acid and TNF in HeLa cells [135]. Similarly, a cyclin B-dependent kinase(s) and/or cyclin E-dependent kinase(s) appear to be involved in DNA damage-induced apoptosis in HL-60 cells [136, 137], and cyclin B appears to be involved in apoptosis in PC-12 cells following nerve growth factor withdrawal [138]. Other work has implicated cyclin-dependent kinases 1 and 2 in the effects of a staurosporine analog in several different human leukemic T cell lines [139], and cyclin D1 has recently been implicated in neuronal cell death [140]. Interestingly, this last study showed that cyclin D-dependent apoptosis was blocked by Rb [140], suggesting that Rb may be a mechanism in the suppression of apoptosis. Precisely how these kinases are activated by the other biochemical signals for apoptosis remains the subject of active investigation.

	Intracellular Acidification

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Work from Eastman's laboratory was the first to clearly implicate alterations in intracellular pH in apoptosis. Working initially with Chinese hamster ovary (CHO) cells, Eastman's laboratory found that apoptosis induced by cancer chemotherapeutics did not clearly involve alterations in intracellular Ca²⁺ concentration, but rather intracellular acidification was identified as the trigger [141]. Further efforts identified a pH-sensitive endonuclease (DNase II) as the most likely endonuclease mediating DNA fragmentation in this system [142]. In their subsequent efforts, they showed that intracellular acidification is also linked to apoptosis in HL-60 myeloid leukemia cells exposed to the topoisomerase-II-active agent etoposide [143] and in an IL-2-dependent T cell line following withdrawal of IL-2 [144]. These results have since been confirmed and extended by other laboratories [145, 146]. Cell acidification is also associated with apoptosis induced by withdrawal of G-CSF from neutrophils [147], and an acid endonuclease has been implicated in DNA fragmentation in this cell type [148]. Apoptosis induced by Fas engagement, cycloheximide, or ultraviolet irradiation in the Jurkat T cell line also involves acidification [149]. Furthermore, inhibition of apoptosis by phorbol esters in neutrophils and HL-60 cells has been linked to intracellular alkalinization due to activation of the Na⁺/H⁺ antiport [62, 144-146, 150]. The latter is attractive as a general mechanism for suppression of apoptosis, as the action of colony stimulating factors in hematopoietic cells is known to involve alkalinization due to activation of the Na⁺/H⁺ antiport. Implicit in this model is the idea that activation of the acid endonuclease is a critical event in apoptosis in certain model systems, which would imply that there are at least two distal pathways for genome fragmentation during the response (Ca²⁺-dependent and -independent).

	Oxygen Radicals

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Several lines of evidence support the involvement of reactive oxygen species ("oxidative stress") in many models of apoptotic cell death [151]. Exogenous oxidants, including redox-active quinones and peroxides, trigger apoptosis in diverse cellular systems [152-154]. In general, low concentrations of the oxidant induce apoptosis, whereas higher levels trigger necrotic cell death [153, 154]. Even in cells that are not exposed to compounds with obvious oxidant properties, the production of reactive oxygen species and depletion of cellular protein and soluble thiols is commonly linked to apoptosis [155-157]. Furthermore, a variety of different antioxidants, including thiols (i.e., N-acetylcysteine), ascorbate, vitamin E, citrate and radical spin traps, have all been shown to block apoptosis [155, 156, 158, 159]. Finally, evidence that the apoptosis suppressors BCL-2 and BCL-X_L may inhibit apoptosis via effects on intracellular redox provides additional evidence for the importance of the mechanism [157, 160, 161]. However, it should be emphasized that hypoxia-induced cell death can involve apoptosis, arguing against an invariant role for oxygen radicals in the response [162-165]. Furthermore, some forms of oxygen toxicity do not appear to involve apoptosis, regardless of the strength of stimulus [166].

Although the mechanisms underlying oxygen radical production in apoptotic cells are still not clear, recent work has supported a role for alterations in mitochondrial function [167]. A precipitous drop in mitochondrial membrane potential (_m) precedes the formation of superoxide radicals, exposure of phosphatidylserine on the surface of cells, DNA fragmentation, and cell death in thymocytes and other cell types undergoing apoptosis [168-172]. This drop in _m is prevented by inhibitors of the ICE proteases and BCL-2 [168, 172], suggesting that it may represent a committed step in the process. A role for mitochondria in apoptosis is attractive, as dysregulation of mitochondrial function has been linked to Ca²⁺ elevations and intracellular acidification [167], and a large portion of BCL-2 has been localized to mitochondria [173]. Furthermore, recent work with cell-free models of apoptosis has demonstrated roles for mitochondrial fractions [174], and in particular, the mitochrondrial protein cytochrome c [175], in promoting ICE family protease/CPP32 activation, PARP cleavage and endonuclease activation.

	Conclusions and Future Directions

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 
Although there is now good evidence implicating specific second messengers and protein kinases in the regulation of apoptosis in diverse model systems, their mechanisms of action are still obscure. Of primary importance for future work is to determine how they regulate the activation of the members of the ICE family (i.e., CPP32), and how this in turn leads to endonuclease activation and cell death. Moreover, although the apoptosis-regulatory properties of the BCL-2 family of polypeptides have been appreciated for several years, little progress has been made toward identifying their mechanisms of action; recent developments linking BCL-2 to various components of the Ras pathway may be particularly informative, as well as evidence that BCL-2 regulates Ca²⁺ compartmentalization and/or oxidative stress. Finally, it is not at all clear why signals that lead to apoptosis in one system promote cell survival in others. Presumably, this indicates that these signaling pathways lie upstream of the cell death effector machinery, and that the cellular response is dictated by the intrinsic programming of the cell. Perhaps investigating the mechanisms by which these second messengers regulate the cell cycle will also provide information on how they regulate programmed cell death.

	Acknowledgments

 
Supported by a grant from the Leukemia Research Foundation, Inc. (to David J. McConkey) and by funds from the Swedish Medical Research Council (to Sten Orrenius).

	References

Top Abstract Introduction Regulation by Ca2+ Protein Kinase C cAMP Ceramide Protein Tyrosine Kinases Cyclin-Dependent Kinases Intracellular Acidification Oxygen Radicals Conclusions and Future... References

 

1. Thompson, CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995;267:1456-1462.[Abstract/Free Full Text]

2. Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980;68:251-305.[Medline]

3. Savill J, Fadok V, Henson P et al. Phagocytic recognition of cells undergoing apoptosis. Immunol Today 1993;14:131-136.[Medline]

4. Oberhammer F, Wilson JW, Dive C et al. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 1993;12:3679-3684.[Medline]

5. Filipski J, Leblanc J, Youdale T et al. Periodicity of DNA folding in higher order chromatin structures. EMBO J 1990;9:1319-1327.[Medline]

6. Brown DG, Sun XM, Cohen GM. Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J Biol Chem 1993;268:3037-3039.[Abstract/Free Full Text]

7. Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 1980;284:555-556.[Medline]

8. Sun XM, Cohen GM. Mg²⁺-dependent cleavage of DNA into kilobase pair fragments is responsible for the initial degradation of DNA in apoptosis. J Biol Chem 1994;269:14857-14860.[Abstract/Free Full Text]

9. Yuan J, Shaham S, Ledoux S et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1ß-converting enzyme. Cell 1993;75:641-652.[Medline]

10. Wang L, Miura M, Bergeron L et al. Ich-1, an ICE/ced-3-related gene, encodes both positive and negative regulators of programmed cell death. Cell 1994;78:739-750.[Medline]

11. Fernandes-Alnemri T, Litwack G, Alnemri ES. CPP32, a novel human apoptotic protein with homology to Caehorhabditis elegans cell death protein ced-3 and mammalian interleukin-1ß-converting enzyme. J Biol Chem 1994;269:30761-30764.[Abstract/Free Full Text]

12. Fernandes-Alnemri T, Litwack G, Alnemri ES. MCH-2, a new member of the apoptotic ced-3/ICE cysteine protease gene family. Cancer Res 1995;55:2737-2742.[Abstract/Free Full Text]

13. Nicholson DW, Ali A, Thornberry NA et al. Identification and inhibition of the ICE/ced-3 protease necessary for mammalian apoptosis. Nature 1995;376:37-43.[Medline]

14. Tewari M, Quan LT, O'Rourke K et al. Yama/CPP32ß, a mammalian homolog of ced-3, is a crmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 1995;81:801-809.[Medline]

15. Martin SJ, Newmeyer DD, Mathias S et al. Cell-free reconstitution of Fas-, UV radiation- and ceramide-induced apoptosis. EMBO J 1995;14:5191-5200.[Medline]

16. Kaufmann SH, Desnoyers S, OttavianoY et al. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res 1993;53:3976-3985.[Abstract/Free Full Text]

17. Lazebnik YA, Kaufmann SH, Desnoyers S et al. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 1994;371:346-347.[Medline]

18. Li P, Allen H, Banerjee S et al. Mice deficient in IL1ß-converting enzyme are defective in production of mature IL-1ß and resistant to endotoxic shock. Cell 1995;80:401-411.[Medline]

19. Fernandes-Alnemri T, Litwack G, Alnemri ES. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein CED-3 and mammalian interleukin 1ß converting enzyme. J Biol Chem 1994;269:30761-30764.

20. Tewari M, Quan LT, O'Rourke K et al. YAMA/CPP32ß, a mammalian homolog of ced-3, is a crmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 1995;81:801-809.

21. Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes. Cell 1994;79:189-192.[Medline]

22. Hengartner MO, Ellis RE, Horvitz HR. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 1992;356:494-499.[Medline]

23. Hengartner MO, Horvitz HR. C. elegans cell survival gene ced-9 encodes a functional homolog of mammalian proto-oncogene bcl-2. Cell 1994;76:665-676.[Medline]

24. Jiang S, Chow SC, Nicotera P et al. Intracellular Ca²⁺ signals activate apoptosis in thymocytes: studies using the Ca²⁺ ATPase inhibitor thapsigargin. Exp Cell Res 1994;212:84-92.[Medline]

25. Kaneko Y, Tsukamoto A. Thapsigargin-induced persistent intracellular calcium pool depletion and apoptosis in human hepatoma cells. Cancer Lett 1994;79:147-155.[Medline]

26. Levick V, Coffey H, D'Mello SR. Opposing effects of thapsigargin on the survival of developing cerebellar granule neurons in culture. Brain Res 1995;676:325-335.[Medline]

27. McConkey DJ, Hartzell P, Nicotera P et al. Calcium-activated DNA fragmentation kills immature thymocytes. FASEB J 1989;3:1843-1849.[Abstract]

28. Wyllie AH, Morris RG, Smith AL et al. Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis. J Pathol 1984;142:67-77.[Medline]

29. Cohen JJ, Duke RC. Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol 1984;132:38-42.[Abstract]

30. Martikainen P, Isaacs J. Role of calcium in the programmed death of rat prostatic glandular cells. Prostate 1990;17:175-187.[Medline]

31. Martikainen P, Kyprianou N, Tucker RW et al. Programmed death of nonproliferating androgen-independent prostatic cancer cells. Cancer Res 1991;51:4693-4700.[Abstract/Free Full Text]

32. Furuya Y, Lundmo P, Short AD et al. The role of calcium, pH, and cell proliferation in the programmed (apoptotic) death of androgen-independent prostatic cancer cells induced by thapsigargin. Cancer Res 1994;54:6167-6175.[Abstract/Free Full Text]

33. McConkey DJ, Orrenius S. The role of calcium in the regulation of apoptosis. J Leuko Biol 1996;59:775-783.[Abstract]

34. McConkey DJ, Nicotera P, Hartzell P et al. Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca²⁺ concentration. Arch Biochem Biophys 1989;269:365-370.[Medline]

35. Khan AA, Soloski MJ, Sharp A et al. Lymphocyte apoptosis: mediation by increased type 3 inositol 1,4,5-trisphosphate receptor. Science 1996;273:503-508.[Abstract]

36. Ankarcrona M, Dypbukt JM, Bonfoco E et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995;15:961-973.[Medline]

37. McConkey DJ, Hartzell P, Duddy SK et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin kills immature thymocytes by Ca²⁺-mediated endonuclease activation. Science 1988;242:256-259.[Abstract/Free Full Text]

38.  Aw TY, Nicotera P, Manzo L et al. Tributyltin stimulates apoptosis in rat thymocytes. Arch Biochem Biophys 1990;283:46-50.[Medline]

39. Dowd DR, MacDonald PN, Komm BS et al. Stable expression of the calbindin-D28K complementary DNA interferes with the apoptotic pathway in T lymphocytes. Mol Endocrinol 1992;6:1843-1848.[Abstract]

40. Ho BK, Alexianu ME, Colom LV et al. Expression of calbindin-D28K in motoneuron hybrid cells after retroviral infection with calbindin-D28K cDNA prevents amyotrophic lateral sclerosis IgG-mediated cytotoxicity. Proc Natl Acad Sci USA 1996;93:6796-6801.[Abstract/Free Full Text]

41. Baffy G, Miyashita T, Williamson JR et al. Apoptosis induced by withdrawal of interleukin-3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced BCL-2 oncoprotein production. J Biol Chem 1993;268:6511-6519.[Abstract/Free Full Text]

42. Lam M, Dubyak G, Chen L et al. Evidence that bcl-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca²⁺ fluxes. Proc Natl Acad Sci USA 1994;91:6569-6573.[Abstract/Free Full Text]

43. Marin MC, Fernandez A, Bick RJ et al. Apoptosis suppression by Bcl-2 is correlated with the regulation of nuclear and cytosolic Ca²⁺. Oncogene 1996;12:2259-2266.[Medline]

44. Rodriguez-Tarduchy G, Collins M, Lopez-Rivas A. Regulation of apoptosis in interleukin-3-dependent hemopoietic cells by interleukin-3 and calcium ionophores. EMBO J 1990;9:2997-3002.[Medline]

45. Whyte MKB, Hardwick SJ, Meagher L et al. Transient elevations of cytosolic free calcium retard subsequent apoptosis in neutrophils in vitro. J Clin Invest 1993;92:446-455.

46. Deckworth TL, Johnson EM, Jr. Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J Cell Biol 1993;123:1207-1222.[Abstract/Free Full Text]

47. Vignaux F, Vivier E, Malissen B et al. TCR/CD3 coupling to Fas-based cytotoxicity. J Exp Med 1995;181:781-786.[Abstract/Free Full Text]

48. Zhivotovsky B, Gahm A, Andarcrona M et al. Multiple proteases are involved in thymocyte apoptosis. Exp Cell Res 1995;221:404-412.[Medline]

49. McConkey DJ. Calcium-dependent, interleukin 1ß-converting enzyme (ICE) inhibitor-insensitive degradation of lamin B1 and DNA fragmentation in isolated thymocyte nuclei. J Biol Chem 1996;271:22398-22406.[Abstract/Free Full Text]

50. deVente JE, Kukoly CA, Bryant WO et al. Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms. Role for p53-independent induction of gadd-45 in initiating death. J Clin Invest 1995;96:1874-1886.

51. deVente J, Kiley S, Garris T et al. Phorbol ester treatment of U937 cells with altered protein kinase C content and distribution induces cell death rather than differentiation. Cell Growth Differ 1995;6:371-382.[Abstract]

52. Kizaki H, Tadakuma T, Odaka C et al. Activation of a suicide process of thymocytes through DNA fragmentation by calcium ionophores and phorbol esters. J Immunol 1989;143:1790-1794.[Abstract]

53. Pongracz J, Tuffley W, Johnson GD et al. Changes in protein kinase C isoenzyme expression associated with apoptosis in U937 myelomonocytic cells. Exp Cell Res 1995;218:430-438.[Medline]

54. Iwata M, Iseki R, Sato K et al. Involvement of protein kinase C-E in glucocorticoid-induced apoptosis in thymocytes. Int Immunol 1994;6:431-438.[Abstract/Free Full Text]

55. Emoto Y, Manome Y, Meinhardt G et al. Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells. EMBO J 1995;14:6148-6156.[Medline]

56. McConkey DJ, Hartzell P, Amador-Perez JF et al. Calcium-dependent killing of immature thymocytes by stimulation via the CD3/T cell receptor complex. J Immunol 1989;143:1801-1806.[Abstract]

57. Illera VA, Perandones CE, Stunz LL et al. Apoptosis in splenic B lymphocytes. Regulation by protein kinase C and IL-4. J Immunol 1993;151:2965-2973.[Abstract]

58. McConkey DJ, Aguilar-Santelises M, Hartzell P et al. Induction of DNA fragmentation in chronic B-lymphocytic leukemia cells. J Immunol 1991;146:1072-1076.[Abstract]

59. Forbes IJ, Zalewski PD, Giannakis C et al. Induction of apoptosis in chronic lymphocytic leukemia cells and its prevention by phorbol ester. Exp Cell Res 1992;198:367-372.[Medline]

60. Bellomo G, Perotti M, Taddei F et al. Tumor necrosis factor induces apoptosis in mammary adenocarcinoma cells by an increase in intranuclear free Ca²⁺ concentration and DNA fragmentation. Cancer Res 1992;52:1342-1346.[Abstract/Free Full Text]

61. Perotti M, Toddei F, Mirabelli F et al. Calcium-dependent DNA fragmentation in human sy-novial cells exposed to cold shock. FEBS Lett 1990;259:331-334.[Medline]

62. Rajotte D, Haddad P, Haman A et al. Role of protein kinase C and the Na⁺/H⁺ antiporter in suppression of apoptosis by granulocyte macrophage colony-stimulating factor and interleukin-3. J Biol Chem 1992;267:9980-9987.[Abstract/Free Full Text]

63. Koseki C, Herzinger D, Al-Awqati Z. Apoptosis in metanephric development. J Cell Biol 1992;119:1327-1333.[Abstract/Free Full Text]

64. Obeid LM, Linardic CM, Karolak LA et al. Programmed cell death induced by ceramide. Science 1993;259:1769-1771.[Abstract/Free Full Text]

65.  Jarvis WD, Kolesnick RN, Fornari FA et al. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci USA 1994;91:73-77.[Abstract/Free Full Text]

66. Jacobson MD, Weil M, Raff MC. Role of Ced-3/ICE-family proteases in staurosporine-induced programmed cell death. J Cell Biol 1996;133:1041-1051.[Abstract]

67. Weil M, Jacobson MD, Coles HS et al. Constitutive expression of the machinery for programmed cell death. J Cell Biol 1996;133:1053-1059.[Abstract/Free Full Text]

68. Pratt RM, Martin GR. Epithelial cell death and cyclic AMP increase during palatal development. Proc Natl Acad Sci USA 1975;72:874-877.[Abstract/Free Full Text]

69. Basile DV, Wood HN, Braun AC. Programming of cells for death under defined experimental conditions: relevance to the tumor problem. Proc Natl Acad Sci USA 1973;70:3055-3059.[Abstract/Free Full Text]

70. Daniel V, Litwack G, Tomkins GM. Induction of cytolysis of cultured lymphoma cells by adenosine 3':5'-cyclic monophosphate and the isolation of resistant variants. Proc Natl Acad Sci USA 1973;70:76-79.[Abstract/Free Full Text]

71. McConkey DJ, Orrenius S, Jondal M. Agents that elevate cAMP stimulate DNA fragmentation in thymocytes. J Immunol 1990;145:1227-1230.[Abstract]

72. Kizaki H, Suzuki K, Tadakuma T et al. Adenosine receptor-mediated accumulation of cyclic AMP-induced T lymphocyte death through internucleosomal DNA cleavage. J Biol Chem 1990;265:5280-5284.[Abstract/Free Full Text]

73. Mentz F, Mossalayi MD, Ouaaz F et al. Involvement of cAMP in CD3/T cell receptor complex- and CD2-mediated apoptosis of human thymocytes. Eur J Immunol 1995;25:1798-1801.[Medline]

74. Lalli E, Sassone-Corsi P, Ceredig R. Block of T lymphocyte differentiation by activation of the cAMP-dependent signal transduction pathway. EMBO J 1996;15:528-537.[Medline]

75.  Aharoni D, Dantes A, Oren M et al. cAMP-mediated signals as determinants for apoptosis in primary granulosa cells. Exp Cell Res 1995;218:271-282.[Medline]

76. Keren-Tal I, Suh BS, Dantes A et al. Involvement of p53 expression in cAMP-mediated apoptosis in immortalized granulosa cells. Exp Cell Res 1995;218:283-295.[Medline]

77. Boe R, Gjertsen BT, Doskeland SO et al. 8-Chloro-cAMP induces apoptotic cell death in a human mammary carcinoma (MCF-7) line. Br J Cancer 1995;72:1151-1159.[Medline]

78. Lomo J, Blomhoff HK, Beiske K et al. TGF-beta 1 and cyclic AMP promote apoptosis in resting human B lymphocytes. J Immunol 1995;154:1634-1643.[Abstract]

79. Han Z, Chatterjee D, Early J et al. Isolation and characterization of an apoptosis-resistant variant of human leukemia HL-60 cells that has switched expression from BCL-2 to BCL-XL. Cancer Res 1996;56:1621-1628.[Abstract/Free Full Text]

80. Vintermyr OI, Gjertsen BT, Lanotte M et al. Microinjected catalytic subunit of cAMP-dependent protein kinase induces apoptosis in myeloid leukemia (IPC-81) cells. Exp Cell Res 1993;206:157-161.[Medline]

81. Duprez E, Gjertsen BT, Bernard O et al. Antiapoptotic effect of heterologously expressed mutant RI (Ala336–Asp) subunit of cAMP kinase I in a rat leukemia cell line. J Biol Chem 1993;268:8332-8340.[Abstract/Free Full Text]

82.  Gruol DJ, Campbell NF, Bourgeois S. Cyclic AMP-dependent protein kinase promotes glucocorticoid receptor function. J Biol Chem 1986;261:4909-4914.[Abstract/Free Full Text]

83. McConkey DJ, Orrenius S, Okret S et al. Cyclic AMP potentiates glucocorticoid-induced endogenous endonuclease activation in thymocytes. FASEB J 1993;7:580-585.[Abstract]

84. D'Mello SR, Galli C, Ciotti T et al. Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP. Proc Natl Acad Sci USA 1993;90:10989-10993.[Abstract/Free Full Text]

85. De A, Boyadjieva NI, Pastorcic M et al. Cyclic AMP and ethanol interact to control apoptosis and differentiation in hypothalamic beta-endorphin neurons. J Biol Chem 1994;269:26697-26705.[Abstract/Free Full Text]

86. Rossi AG, Cousin JM, Dransfield I et al. Agents that elevate cAMP inhibit human neutrophil apoptosis. Biochem Biophys Res Commun 1995;217:892-899.[Medline]

87. Messmer UK, Lapetina EG, Brune B. Nitric oxide-induced apoptosis in RAW 264.7 macrophages is antagonized by protein kinase C- and protein kinase A-activating compounds. Mol Pharmacol 1995;47:757-765.[Abstract]

88. Flaws JA, DeSanti A, Tilly KI et al. Vasoactive intestinal peptide-mediated suppression of apoptosis in the ovary: potential mechanisms of action and evidence of a conserved antiatretogenic role through evolution. Endocrinol 1995;136:4351-4359.[Abstract]

89. Lee MR, Liou ML, Yang YF et al. cAMP analogs prevent activation-induced apoptosis of T cell hybridomas. J Immunol 1993;151:5208-5217.[Abstract]

90.  Hoshi S, Furutani-Seiki M, Seto M et al. Prevention of TCR-mediated apoptosis by the elevation of cAMP. Int Immunol 1994;6:1081-1089.[Abstract/Free Full Text]

91. Goetzl EJ, An S, Zeng L. Specific suppression by prostaglandin E2 of activation-induced apoptosis of human CD4⁺CD8⁺ T lymphoblasts. J Immunol 1995;154:1041-1047.[Abstract]

92. Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci 1995;20:73-77.[Medline]

93. Gulbins E, Bissonnette R, Mahboubi A et al. FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 1995;2:341-351.[Medline]

94. Tepper CG, Jayadev S, Liu B et al. Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity. Proc Natl Acad Sci USA 1995;92:8443-8447.[Abstract/Free Full Text]

95. Haimovitz-Friedman A, Kan CC, Ehleiter D et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med 1994;180:525-535.[Abstract/Free Full Text]

96. Bose R, Verheij M, Haimovitz-Friedman A et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 1995;82:405-414.[Medline]

97.  White K, Tahaoglu E, Steller H. Cell killing by the Drosophila gene reaper. Science 1996;271:805-810.[Abstract]

98.  Ito A, Horigame K. Ceramide prevents neuronal programmed cell death induced by nerve growth factor deprivation. J Neurochem 1995;65:463-466.[Medline]

99. Wolff RA, Dobrowsky RT, Bielawska A et al. Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J Biol Chem 1994;269:19605-19606.[Abstract/Free Full Text]

100. Verheij M, Bose R, Lin XH et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 1996;380:75-79.[Medline]

101. Sawai H, Okazaki T, Yamamoto H et al. Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells. J Biol Chem 1995;270:27326-27331.[Abstract/Free Full Text]

102. Trent JC, McConkey DJ, Loughlin SM et al. Ras signaling in tumor necrosis factor-induced apoptosis. EMBO J 1996;15:4497-4505.[Medline]

103. Yao B, Zhang Y, Delikat S et al. Phosphorylation of Raf by ceramide-activated protein kinase. Nature 1995;378:307-310.[Medline]

104. Jarvis WD, Fornari FA, Jr., Browning JL et al. Attenuation of ceramide-induced apoptosis by diglyceride in human myeloid leukemia cells. J Biol Chem 1994;269:31685-31692.[Abstract/Free Full Text]

105. Cuvillier O, Pirianov G, Kleuser B et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 1996;381:800-803.[Medline]

106. Dbaibo GS, Pushkareva MY, Jayadev S et al. Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Proc Natl Acad Sci USA 1995;92:1347-1351.[Abstract/Free Full Text]

107. McConkey DJ, Goodrich D, Bucana C et al. The human retinoblastoma gene product suppresses ceramide-induced apoptosis in human bladder tumor cells. Oncogene 1996 (in press).

108. Laneuville P, Timm M, Hudson AT. bcr/abl expression in 32D cl3(G) cells inhibits apoptosis induced by protein tyrosine kinase inhibitors. Cancer Res 1994;54:1360-1366.[Abstract/Free Full Text]

109. Otani H, Erdos M, Leonard WJ. Tyrosine kinase(s) regulate apoptosis and bcl-2 expression in a growth factor-dependent cell line. J Biol Chem 1993;268:22733-22736.[Abstract/Free Full Text]

110. Yousefi S, Green DR, Blaser K et al. Protein-tyrosine phosphorylation regulates apoptosis in human eosinophils and neutrophils. Proc Natl Acad Sci USA 1994;91:10868-10872.[Abstract/Free Full Text]

111. Yee NS, Paek I, Besmer P. Role of kit ligand in proliferation and suppression of apoptosis in mast cells: basis for radiosensitivity of white spotting and Steel mutant mice. J Exp Med 1994;179:1777-1787.[Abstract/Free Full Text]

112. Iemura A, Tsai M, Ando A et al. The c-kit ligand, stem cell factor, promotes mast cell survival by suppressing apoptosis. Am J Pathol 1994;144:321-328.[Abstract]

113. Caceres-Cortes J, Rajotte D, Dumouchel J et al. Product of the Steel locus suppresses apoptosis in hemopoietic cells. Comparison with pathways activated by granulocyte macrophage colony-stimulating factor. J Biol Chem 1994;269:12084-12091.[Abstract/Free Full Text]

114. Abrahamson JL, Lee JM, Bernstein A. Regulation of p53-mediated apoptosis and cell cycle arrest by Steel factor. Mol Cell Biol 1995;15:6953-6960.[Abstract]

115. Tilly JL, Billig H, Kowalski KI et al. Epidermal growth factor and basic fibroblast growth factor suppress the spontaneous onset of apoptosis in cultured rat ovarian granulosa cells and follicles by a tyrosine kinase-dependent mechanism. Mol Endocrinol 1992;6:1942-1950.[Abstract]

116. Wu X, Fan Z, Masui H et al. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 1995;95:1897-1905.

117. Evans CA, Owen-Lynch PJ, Whetton AD et al. Activation of the Abelson tyrosine kinase activity is associated with suppression of apoptosis in hemopoietic cells. Cancer Res 1993;53:1735-1738.[Abstract/Free Full Text]

118. Cortez D, Kadlec L, Prendergast AM. Structural and signaling requirements for BCL-ABL-mediated transformation and inhibition of apoptosis. Mol Cell Biol 1995;15:5531-5541.[Abstract]

119. McGahon AJ, Nishioka WK, Martin SJ et al. Regulation of the Fas apoptotic cell death pathway by Abl. J Biol Chem 1995;270:22625-22631.[Abstract/Free Full Text]

120. Chapman RS, Whetton AD, Dive C. The suppression of drug-induced apoptosis by activation of v-ABL protein tyrosine kinase. Cancer Res 1994;54:5131-5137.[Abstract/Free Full Text]

121. Chapman RS, Whetton AD, Chresta CM et al. Characterization of drug resistance mediated via the suppression of apoptosis by Abelson protein tyrosine kinase. Mol Pharmacol 1995;48:334-343.[Abstract]

122. Uckun FM, Tuel-Ahlgren L, Song CW et al. Ionizing radiation stimulates unidentified tyrosine-specific protein kinases in human B-lymphocyte precursors, triggering apoptosis and clonogenic cell death. Proc Natl Acad Sci USA 1992;89:9005-9009.[Abstract/Free Full Text]

123. Nakashima I, Zhang YH, Rahman SM et al. Evidence of synergy between Thy-1 and CD3/TCR complex in signal delivery to murine thymocytes for cell death. J Immunol 1991;147:1153-1162.[Abstract]

124. Nakashima I, Pu MY, Hamaguchi H et al. Pathway of signal delivery to murine thymocytes triggered by co-crosslinking CD3 and Thy-1 for cellular DNA fragmentation and growth inhibition. J Immunol 1993;151:3511-3520.[Abstract]

125. McConkey DJ, Fosdick L, D'Adamio L et al. Co-receptor (CD4/CD8) engagement enhances CD3-induced apoptosis in thymocytes. Implications for negative selection. J Immunol 1994;153:2436-2443.[Abstract]

126. Waddick KG, Chae HP, Tuel-Ahlgren L et al. Engagement of the CD19 receptor on human B-lineage leukemia cells activates LCK tyrosine kinase and facilitates radiation-induced apoptosis. Radiat Res 1993;136:313-319.[Medline]

127. Shi Y, Glynn JM, Guilbert LJ et al. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 1992;257:212-214.[Abstract/Free Full Text]

128. Askew DS, Ashmun RA, Simmons BC et al. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 1991;6:1915-1922.[Medline]

129. Evan GI, Wyllie H, Gilbert CS et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992;69;119-128.[Medline]

130. Clarke AR, Purdie CA, Harrison DJ et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 1993;362:849-852.[Medline]

131. Lowe SW, Schmitt EM, Smith SW et al. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 1993;362:847-849.[Medline]

132. Lowe SW, Ruley HE, Jacks T et al. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993;74:957-967.[Medline]

133. Shi L, Nishioka WK, Th'ng J et al. Premature activation of p34cdc2 required for apoptosis. Science 1994;263:1143-1145.[Abstract/Free Full Text]

134. Hoang AT, Cohen KJ, Barrett JF et al. Participation of cyclin A in myc-induced apoptosis. Proc Natl Acad Sci USA 1994;91:6875-6879.[Abstract/Free Full Text]

135. Meikrantz W, Gisselbrecht S, Tam SW et al. Activation of cyclin A-dependent protein kinases during apoptosis. Proc Natl Acad Sci USA 1994;91:3754-3758.[Abstract/Free Full Text]

136. Shimizu T, O'Connor PM, Kohn KW et al. Unscheduled activation of cyclin B1/cdc2 kinase in human promyelocytic leukemia cell line HL-60 cells undergoing apoptosis induced by DNA damage. Cancer Res 1995;55:228-231.[Abstract/Free Full Text]

137. Dou QP, An B, Yu C. Activation of cyclin E-dependent kinase by DNA damage signals during apoptosis. Biochem Biophys Res Commun 1995;214:771-780.[Medline]

138. Gao CY, Zelenka PS. Induction of cyclin B and H1 kinase activity in a