Abnormalities of the Immune System Induced by Dysregulated bcl-2 Expression in Transgenic Mice

Strasser, Andreas; Harris, Alan W.; Vaux, David; Webb, Elizabeth; Bath, Mary L.; Adams, Jerry M.; Cory, Suzanne

doi:10.1007/978-3-642-75889-8_22

Cited by 96 publications

(105 citation statements)

References 13 publications

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“…In contrast, neither mortality nor accumulation of autoantibodies was observed in CD19Cre ϩ Bax fl/Ϫ Bak Ϫ/Ϫ mice by 35 weeks of age, suggesting that deficiency of Bax and Bak in cells other than B cells is also required to cause a complex immune disease. This cumulative mortality owing to the development of autoimmune disease is also observed in Bim Ϫ/Ϫ mice and in mice overexpressing Bcl-2 in B cells (13,14,22). The overlapping phenotype of these mutant mice fits with the current model of the function of BCL-2 family members in vivo in immune cells, where BH3-only proteins act as upstream sentinels competing for downstream pro-and antiapoptotic BCL-2 members in response to apoptotic or survival signals, suggesting that stapled BH3 peptides may be a promising therapeutic for autoimmune diseases (11,39).…”

Section: Discussionmentioning

confidence: 81%

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Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease

Takeuchi

Fisher²,

Suh³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

191

198

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T he development and maintenance of B lymphocytes is regulated at multiple checkpoints (1). Newly generated pro-B cells undergo B cell antigen-receptor (BCR) recombination in fetal liver and adult bone marrow (BM). B cells that fail to produce a functional BCR lack survival signals and thus undergo death by neglect (2). B cells that express surface BCRs that interact with self-antigens with too high affinity may be eliminated, at least in part, by apoptotic cell death, as well as anergy and receptor editing (3, 4). Immature B cells that successfully pass through developmental checkpoints in the BM migrate to the spleen as transitional B cells and undergo further maturation steps (5). The number of B lymphocytes in BM and secondary lymphoid organs is kept under tight control. Disruption of this homeostasis and accumulation of excess lymphocytes may give rise to the development of autoimmunity or malignancy.BCL-2 family member proteins are requisite for the maintenance of lymphocyte numbers by regulating an intrinsic apoptosis pathway (2, 6-8). The antiapoptotic members, including BCL-2, BCL-xL, and MCL-1, display sequence conservation in four BCL-2 homology domains (BH1-BH4). Multidomain proapoptotic members, including BAX and BAK, possess the BH1, BH2, and BH3 domains. The ''BH3-only'' proteins, including BID, BAD, BIM, NOXA, and PUMA, show homology only within this single amphipathic ␣-helical segment. BH3-only molecules function as upstream sentinels that sense cellular abnormalities, such as lack of survival signals or DNA damage. Activated BH3-only molecules trigger the oligomerization of multidomain proapoptotic BCL-2 members by sequestering antiapoptotics and͞or by direct activation of BAX or BAK (9-12). Oligomerization of BAX or BAK leads to the release of cytochrome c from mitochondria to the cytoplasm, causing the formation of the apoptosome and execution of cell death.The role of the BCL-2 family in B cell homeostasis has been analyzed intensively by using mouse models that either have overexpression or deletion of BCL-2 family molecules (2, 13-15). Overexpression of BCL-2 protects B cells from death by neglect and by negative selection, and causes the accumulation of B cells (13,16,17). In addition, lymphocytes from Bcl-2 transgenic mice show defects in cell cycle progression (18,19). In contrast, targeted deletion of the Bcl-2 gene in mice resulted in the massive loss of mature lymphocytes due to apoptosis, as well as increased turnover of thymocytes (15,20). Deletion of another antiapoptotic, MCL-1, resulted in the loss of B cells throughout their development (21). Among BH3 only molecules, only BIM is implicated in the homeostatic maintenance of lymphocytes. Bim-deficient mice are reported to show abnormal development of T lymphocytes and accumulation of lymphocytes in secondary lymphoid organs (20,22). Bim Ϫ/Ϫ B cells were resistant to apoptosis induced by the absence of IL-7 receptor signaling and by BCR ligation, and showed defective negative selection of B cells in vivo (23,24). In addition, Bi...

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Section: Discussionmentioning

confidence: 81%

“…The role of the BCL-2 family in B cell homeostasis has been analyzed intensively by using mouse models that either have overexpression or deletion of BCL-2 family molecules (2,(13)(14)(15). Overexpression of BCL-2 protects B cells from death by neglect and by negative selection, and causes the accumulation of B cells (13,16,17).…”

mentioning

confidence: 99%

Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease

Takeuchi

Fisher²,

Suh³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

191

198

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“…The generation of mice homozygous for the syk null mutation (syk -/-) and of 3-83 ?ˇ-Tg and bcl-2-Tg mice has been described [5, 13,39]. All mice were backcrossed for five generations onto the B10.D2 background.…”

Section: Micementioning

confidence: 99%

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

2004

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In this study we set out to test whether Syk was required for negative selection of immature B cells. B cells expressing a B cell antigen receptor (BCR) transgene (3-83, anti-H-2K k ) underwent negative selection independently of Syk in both fetal liver organ culture and radiation chimera models. Furthermore, Syk-independent negative selection was not reversed by transgenic overexpression of Bcl-2. Receptor editing was not apparent in Syk-deficient B cells, presumably as a consequence of the failure of mature edited B cells to develop in the absence of Syk. Interestingly, light chain isotype exclusion by the BCR transgene failed in the absence of Syk. We observed a dramatic reduction in the overall BCR-mediated tyrosine phosphorylation of cellular proteins in Syk-deficient immature B cells. However, the tyrosine phosphorylation of a number of substrates including phospholipase C + 2, although reduced, was not completely abrogated. BCR ligation triggered an increase in calcium flux in the absence of Syk. Thus signaling events that mediate negative selection can still occur in the absence of Syk. This may be due to redundancy with zeta-associated protein 70 (ZAP-70), which we demonstrate to be expressed in immature B cells.

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“…This interpretation was further supported by genetic evidence. We crossed Rad50 S/S with Eµ-Bcl2 mice, which carry a transgene of the anti-apoptotic BCL2 gene (Strasser et al 1990). This transgene increases resistance to apoptosis in B and T lymphocytes (Strasser et al 1991a,b).…”

Section: Rad50 S/s Cellular Attrition Is Due To Apoptosismentioning

confidence: 99%

“…), and Eµ-Bcl2 mice, survival, and genotyping have been described (Strasser et al 1990;Barlow et al 1996;Luo et al 1999;Bender et al 2002;Hirao et al 2002;Williams et al 2002;Theunissen et al 2003;Kitagawa et al 2004). All mice maintained on mixed 129/ SvEv and C57BL6 background.…”

Section: Rad50 S/smentioning

confidence: 99%

The Rad50^S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor

Morales¹,

Theunissen²,

Kim³

et al. 2005

Genes Dev.

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Genetic and cytologic data from Saccharomyces cerevisiae and mammals implicate the Mre11 complex, consisting of Mre11, Rad50, and Nbs1, as a sensor of DNA damage, and indicate that the complex influences the activity of ataxia-telangiectasia mutated (ATM) in the DNA damage response. Rad50 S/S mice exhibit precipitous apoptotic attrition of hematopoietic cells. We generated ATM-and Chk2-deficient Rad50 S/S mice and found that Rad50 S/S cellular attrition was strongly ATM and Chk2 dependent. The hypomorphic Mre11 ATLD1 and Nbs1 ⌬B alleles conferred similar rescue of Rad50 S/S -dependent hematopoietic failure. These data indicate that the Mre11 complex activates an ATM-Chk2-dependent apoptotic pathway. We find that apoptosis and cell cycle checkpoint activation are parallel outcomes of the Mre11 complex-ATM pathway. Conversely, the Rad50 S mutation mitigated several phenotypic features of ATM deficiency. We propose that the Rad50 S allele is hypermorphic for DNA damage signaling, and that the resulting constitutive low-level activation of the DNA damage response accounts for the partial suppression of ATM deficiency in Rad50 S/S Atm −/− mice.[Keywords: Checkpoints; DNA damage signaling; apoptosis]Supplemental material is available at http://www.genesdev.org.

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Abnormalities of the Immune System Induced by Dysregulated bcl-2 Expression in Transgenic Mice

Cited by 96 publications

References 13 publications

Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease

Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

The Rad50^S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor

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Abnormalities of the Immune System Induced by Dysregulated bcl-2 Expression in Transgenic Mice

Cited by 96 publications

References 13 publications

Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease

Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor

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The Rad50^S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor