Showing papers by "Andreas Strasser published in 2003"
TL;DR: In mice with either noxa or puma disrupted, decreased DNA damage–induced apoptosis in fibroblasts is observed, although only loss of Puma protected lymphocytes from cell death, and Puma deficiency protected cells against diverse p53-independent cytotoxic insults.
Abstract: Apoptosis provoked by DNA damage requires the p53 tumor suppressor, but which of the many p53-regulated genes are required has remained unknown. Two genes induced by this transcription factor, noxa and puma (bbc3), stand out, because they encode BH3-only proteins, proapoptotic members of the Bcl-2 family required to initiate apoptosis. In mice with either noxa or puma disrupted, we observed decreased DNA damage-induced apoptosis in fibroblasts, although only loss of Puma protected lymphocytes from cell death. Puma deficiency also protected cells against diverse p53-independent cytotoxic insults, including cytokine deprivation and exposure to glucocorticoids, the kinase inhibitor staurosporine, or phorbol ester. Hence, Puma and Noxa are critical mediators of the apoptotic responses induced by p53 and other agents.
1,309 citations
TL;DR: The role of the Bcl-2 protein family and to a lesser extent that of death receptors (members of the tumor necrosis factor receptor family with a death domain) in the control of lymphoid and myeloid cell survival is described.
Abstract: Apoptotic cell death plays a critical role in the development and functioning of the immune system. During differentiation, apoptosis weeds out lymphocytes lacking useful antigen receptors and those expressing dangerous ones. Lymphocyte death is also involved in limiting the magnitude and duration of immune responses to infection. In this review, we describe the role of the Bcl-2 protein family, and to a lesser extent that of death receptors (members of the tumor necrosis factor receptor family with a death domain), in the control of lymphoid and myeloid cell survival. We also consider the pathogenic consequences of failure of apoptosis in the immune system.
402 citations
TL;DR: It is reported that B lymphocytes lacking the pro-apoptotic Bcl-2 family member Bim are refractory to apoptosis induced by BCR ligation in vitro, and it is demonstrated that Bim is a critical player in BCR-mediated apoptosis and in B lymphocyte deletion.
Abstract: During development, the stochastic process assembling the genes encoding antigen receptors invariably generates B and T lymphocytes that can recognize self-antigens. Several mechanisms have evolved to prevent the activation of these cells and the concomitant development of autoimmune disease. One such mechanism is the induction of apoptosis in developing or mature B cells by engagement of the B cell antigen receptor (BCR) in the absence of T cell help. Here we report that B lymphocytes lacking the pro-apoptotic Bcl-2 family member Bim are refractory to apoptosis induced by BCR ligation in vitro. The loss of Bim also inhibited deletion of autoreactive B cells in vivo in two transgenic systems of B cell tolerance. Bim loss prevented deletion of autoreactive B cells induced by soluble self-antigen and promoted accumulation of self-reactive B cells developing in the presence of membrane-bound self-antigen, although their numbers were considerably lower compared with antigen-free mice. Mechanistically, we determined that BCR ligation promoted interaction of Bim with Bcl-2, inhibiting its survival function. These findings demonstrate that Bim is a critical player in BCR-mediated apoptosis and in B lymphocyte deletion.
295 citations
TL;DR: Bim is dispensable for viral clearance but is necessary for the death of activated T cells when immune responses are terminated, which has implications for the therapeutic manipulation of immune responses to infections and immunization.
Abstract: We used mutant Fas-deficient (lpr) or Bim-deficient mice to investigate the role of the death receptor and Bcl-2-regulated apoptotic pathways in terminating a physiological T cell response to herpes simplex virus infection. In WT and lpr mice CD8+ antigen-specific T cells were deleted after viral clearance. In contrast, the immune response was not terminated in Bim-deficient mice despite viral clearance, and CD8+ antigen-specific T cells accumulated in the spleen. Thus, Bim is dispensable for viral clearance but is necessary for the death of activated T cells when immune responses are terminated. These findings have implications for the therapeutic manipulation of immune responses to infections and immunization.
256 citations
TL;DR: Current knowledge of the molecular control of cell death is described and the role of pro- and anti-apoptotic members of the Bcl-2 protein family in tumourigenesis andAnti-cancer therapy is discussed.
253 citations
TL;DR: It is demonstrated that ubiquitylation‐dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.
Abstract: Osteoclasts (OCs) undergo rapid apoptosis without trophic factors, such as macrophage colony‐stimulating factor (M‐CSF). Their apoptosis was associated with a rapid and sustained increase in the pro‐apoptotic BH3‐only Bcl‐2 family member Bim. This was caused by the reduced ubiquitylation and proteasomal degradation of Bim that is mediated by c‐Cbl. Although the number of OCs was increased in the skeletal tissues of bim−/− mice, the mice exhibited mild osteosclerosis due to reduced bone resorption. OCs differentiated from bone marrow cells of bim−/− animals showed a marked prolongation of survival in the absence of M‐CSF, compared with bim+/+ OCs, but the bone‐resorbing activity of bim−/− OCs was significantly reduced. Overexpression of a degradation‐resistant lysine‐free Bim mutant in bim−/− cells abrogated the anti‐apoptotic effect of M‐CSF, while wild‐type Bim did not. These results demonstrate that ubiquitylation‐dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.
252 citations
TL;DR: Results indicate that the BH3-only protein Bim and possibly also Bmf are critical initiators of spontaneous and drug-induced apoptosis of granulocytes, whereas Bcl-2, bcl-w, and Bax act in a redundant manner in regulating granulocyte survival and death, respectively.
160 citations
TL;DR: Some of the experiments using transgenic and knockout mice, which overexpress or lack apoptosis regulators, that led to discoveries on how life and death decisions are made during development and functioning of the immune system are described.
Abstract: The stochastic nature of rearrangement and diversification of the gene segments encoding immunoglobulins (Igs) and T cell receptors (TCRs) inevitably gives rise to immature B and T lymphocytes that lack antigen receptors or express useless or dangerous (self-antigen-specific) ones. Signaling through antigen receptors promotes survival, proliferative expansion and further differentiation of useful cells and deletion of the useless and dangerous ones. During immune responses, pathogen-specific B and T lymphocytes, as well as cells of the innate immune system, undergo extensive proliferation and develop effector functions, such as antibody secretion, cytotoxicity or cytokine production. To prevent tissue damage by these effector molecules, activated lymphocytes are removed when an infection has been overcome. Together with other mechanisms, including developmental arrest and induction of unresponsiveness (anergy), programmed cell death (apoptosis) of autoreactive lymphocytes safeguards immunological tolerance to self and assists in the development of an effective immune system. We have been investigating the molecular mechanisms that control programmed cell death. This review describes some of our experiments using transgenic and knockout mice, which overexpress or lack apoptosis regulators, that led to discoveries on how life and death decisions are made during development and functioning of the immune system.
83 citations
TL;DR: The seemingly paradoxical observations that caspase 8 is critical for both activation and death of cells of the immune system are the focus of this review.
Abstract: Members of the caspase family of aspartate-specific cysteine proteases are best known for their involvement in apoptosis (human caspases 2, 3, 6, 7, 8, 9, 10; mouse caspases 2, 3, 6, 7, 8, 9, 12) and the maturation of cytokines such as IL-1 and IL-18 (human caspases 1, 4, 5; mouse caspases 1, 11; Thornberry and Lazebnik 1998; Shi 2002) . Recently, however, there have been a number of reports suggesting that caspases, in particular caspase 8, may have an additional role in the immune system promoting lymphocyte activation and proliferation (Chun et al. 2002; Salmena et al. 2003). The seemingly paradoxical observations that caspase 8 is critical for both activation and death of cells of the immune system are the focus of this review.
79 citations
TL;DR: Investigation of intrathymic negative selection of TRAIL-deficient thymocytes, using four well-established models, was unable to demonstrate a role for TRAIL signaling in any of these models, suggesting that this pathway is not a critical factor for thymocyte negative selection.
Abstract: The molecular basis of thymocyte negative selection, which plays a critical role in establishing and maintaining immunological tolerance, is not yet resolved. In particular, the importance of the death receptor subgroup of the tumor necrosis factor (TNF)-family has been the subject of many investigations, with equivocal results. A recent report suggested that TRAIL was a critical factor in this process, a result that does not fit well with previous studies that excluded a role for the FADD-caspase 8 pathway, which is essential for TRAIL and Fas ligand (FasL) signaling, in negative selection. We have investigated intrathymic negative selection of TRAIL-deficient thymocytes, using four well-established models, including antibody-mediated TCR/CD3 ligation in vitro, stimulation with endogenous superantigen in vitro and in vivo, and treatment with exogenous superantigen in vitro. We were unable to demonstrate a role for TRAIL signaling in any of these models, suggesting that this pathway is not a critical factor for thymocyte negative selection.
74 citations
TL;DR: The model described here is aimed to serve as a paradigm for how Rel/NF-κB family members control survival in different cell types during differentiation and in response to the plethora of signals that impinge on this master transcriptional regulatory pathway.
TL;DR: Low amounts of B fk were found in stomach, ovary, bone marrow and spleen, but its level in the mammary gland rose markedly during pregnancy, suggesting that Bfk may play a role in mammary development.
Abstract: Proteins of the Bcl-2 family are critical regulators of apoptosis. Proapoptotic members, like Bax, contain three of the four Bcl-2 homology regions (BH1-3), while BH3-only proteins, like Bim, possess only the short BH3 motif. Database searches revealed Bfk, an unusual novel member of the Bcl-2 family that contains a BH2 and BH3 region but not BH1 or BH4. Bfk is thus most closely related to Bcl-GL. It lacks a C-terminal membrane anchor and is cytosolic. Enforced expression of Bfk weakly promoted apoptosis and antagonized Bcl-2's prosurvival function. Like Bcl-GL, Bfk did not bind to any Bcl-2 family members, even though its BH3 motif can mediate association with prosurvival proteins. Low amounts of Bfk were found in stomach, ovary, bone marrow and spleen, but its level in the mammary gland rose markedly during pregnancy, suggesting that Bfk may play a role in mammary development.
TL;DR: The studies show that Bim deficiency does not modify the Lurcher phenotype, ruling out an indispensable role for Bim in this neurodegenerative disease.
Abstract: Lurcher (lc) mice have a semi-dominant mutation in the gene encoding the δ2 glutamate receptor (GRID2). The resulting constitutive activity of this receptor in heterozygous +/lc (grid+/lc) and homozygous (gridlc/lc) mice leads to the death of all cerebellar Purkinje cells and most afferent granule neurons. Some studies have indicated that the death of Purkinje cells occurs by apoptosis, and the secondary loss of granule neurons has been shown to require the pro-apoptotic Bcl-2 family member Bax. The BH3-only protein Bim has been shown to contribute to cytokine withdrawal-induced apoptosis of sympathetic neurons and to be responsible for the kidney degeneration in mice lacking the pro-survival protein Bcl-2. Because Bim is expressed strongly in cerebellar Purkinje cells, we have examined whether it has a role in their death in mutant Lurcher mice. Our studies show that Bim deficiency does not modify the Lurcher phenotype, ruling out an indispensable role for Bim in this neurodegenerative disease. © 2003 Wiley-Liss, Inc.
TL;DR: It is demonstrated that, as in the autoimmune-prone MRL stain, the NOD genetic background promotes lupus nephritis-like pathology and extensive lymphadenopathy when lpr is present and loss of TNFRI does not exacerbate the pathology caused by deficiency in Fas.
Abstract: Fas and TNFRI, two members of the tumor necrosis factor receptor family with an intracellular death domain, each play critical roles in apoptotic death of lymphocytes and certain other cell types. We determined the overlapping functions of Fas and TNFRI by breeding non-obese diabetic (NOD) mutant mice that lacked both receptors. NODlpr mice developed extensive lymphadenopathy, splenomegaly, CD4(-)CD8(-) B220(+) alpha beta TCR(+) T cells and autoimmune kidney disease. This pathology was not modified by concomitant deficiency in TNFRI as was reported for lpr mice on a B6 background. NODlpr mice lacking CD8(+) T cells, because of a null mutation in beta(2)-microglobulin (beta(2)m), also developed a similar disease profile to NODlpr animals, but the CD4(-)CD8(-) B220(+) alpha beta TCR(+) T cells now derived from a CD4(+) T cell lineage. These results demonstrate that, as in the autoimmune-prone MRL stain, the NOD genetic background promotes lupus nephritis-like pathology and extensive lymphadenopathy when lpr is present. Loss of TNFRI does not exacerbate the pathology caused by deficiency in Fas and loss of beta(2)m does not reduce it.
Patent•
23 Oct 2003
TL;DR: Guo et al. as discussed by the authors identified a new member of the Bcl-2 family of proteins, referred to as "Bfk" for 'Bcl2 family kin', which lacks a C-terminal membrane anchor and is cytosolic.
Abstract: The present invention is predicated in part on the identification of a novel member of the Bcl-2 family of proteins. The protein is referred to herein as 'Bfk' for 'Bcl-2 family kin'. It is proposed that Bfk forms a new sub-family of Bcl-2 members along with Bcl-GL (Guo et al., 2001, supra). Bfk lacks a C-terminal membrane anchor and is cytosolic. On transfection, Bfk displays pro-apoptotic activity and antagonizes the pro-survival function of Bcl-2. Unlike other pro-apoptotic family members, however, Bfk does not bind to Bcl-2-like proteins, even though its BH3 motif mediates association. Bfk also fails to interact with Bax or BH3-only proteins such as Bim. Thus, proteins like Bfk and Bcl-GL, possessing only the BH3 and BH2 regions, represent a new pro-apoptotic sub-group in the Bcl-2 family.