DOI: 10.1126/science.286.5445.1735. Proapoptotic Bcl-2 Relative Bim Required for Certain Apoptotic Responses, Leukocyte Homeostasis, and to Preclude Autoimmunity

Proapoptotic Bcl-2 Relative Bim Required for Certain Apoptotic Responses, Leukocyte Homeostasis, and to Preclude Autoimmunity

10.1126/science.286.5445.1735

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim, that share only the BH3 domain with this family. Gene targeting in mice revealed important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T cell development was perturbed, and most older mice accumulated plasma cells and succumbed to autoimmune kidney disease. Lymphocytes were refractory to apoptotic stimuli such as cytokine deprivation, calcium ion flux, and microtubule perturbation but not to others. Thus, Bim is required for hematopoietic homeostasis and as a barrier to autoimmunity. Moreover, particular death stimuli appear to activate apoptosis through distinct BH3-only proteins.

Bibliography

Bouillet, P., Metcalf, D., Huang, D. C. S., Tarlinton, D. M., Kay, T. W. H., KoÌntgen, F., Adams, J. M., & Strasser, A. (1999). Proapoptotic Bcl-2 Relative Bim Required for Certain Apoptotic Responses, Leukocyte Homeostasis, and to Preclude Autoimmunity. Science, 286(5445), 1735â1738.

Authors 8

Philippe Bouillet (first)
Donald Metcalf (additional)
David C. S. Huang (additional)
David M. Tarlinton (additional)
Tom W. H. Kay (additional)
Frank Köntgen (additional)
Jerry M. Adams (additional)
Andreas Strasser (additional)

References 37 Referenced 1,229

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Strasser A., Huang D. C. S., Vaux D. L., Biochim. Biophys. Acta 1333, F151 (1997). / Biochim. Biophys. Acta by Strasser A. (1997)
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In the targeting vector (see Fig. 1A) prepared from 129SV/J DNA the 110–base pair (bp) BH3-containing exon is replaced by the PGK neo expression cassette flanked by loxP sites (20). Splicing of the remaining bim exons will produce a frameshift which introduces a stop codon 12 bp downstream. Linearized targeting vector (30 mg) was electroporated into W9.5 ES cells. Hind III–digested DNA from 133 G418-resistant colonies was screened by Southern blotting with a 3-kb external probe (1.7 kb + 1.3 kb Bgl II fragments) for the 8-kb Hind III fragment. Two independent ES clones bearing a single targeted copy of the bim locus were microinjected into C57BL/6 blastocysts. Chimeric agouti-colored offspring were backcrossed to C57BL/6 mice or C57BL/6-Deleter mice (11).
Schwenk F., Baron U., Rajewsky K., Nucleic Acids Res. 23, 5080 (1995). (10.1093/nar/23.24.5080) / Nucleic Acids Res. by Schwenk F. (1995)
The impact of the truncated Bim polypeptide (Bim KO ) was investigated by stable or transient overexpression in four cell lines. Bim KO did not bind to Bcl-2 or Bim and had no effect on apoptosis induced by cytokine withdrawal γ-irradiation or treatment with dexamethasone or staurosporine. It also did not affect Bcl-2 prosurvival activity.
Some bim − / − males mated with bim +/− females routinely produced 50% bim − / − pups but others sired hardly any bim − / − offspring. Because of the incomplete penetrance of the lethality an inbred genetic background and large numbers of fetuses of different gestation ages will be required to identify the developmental defect imposed by Bim deficiency.
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Lysates precleared with an isotype-matched antibody (Ter119) were precipitated with rat anti-Bim monoclonal antibody 5E5 or 14A8 (21) and protein G– Sepharose. The washed immune complexes were fractionated electrophoretically on SDS–polyacrylamide gels and proteins transferred onto polyvinylidene difluoride membranes (Millipore). Bim protein was detected with 5E5 or 14A8 followed by a mouse anti-rat immunoglobulin reagent and ECL reaction (Amersham Pharmacia).
Peripheral blood erythrocytes and leukocytes were enumerated in a hemocytometer or with a ZM model Coulter counter and platelets were counted in a Sysmex NE8000 counter (TOA Kobe Japan). Suspensions of cells from thymus spleen lymph nodes bone marrow or blood were stained with cell type-specific monoclonal antibodies that had been purified on protein G–Sepharose and conjugated with fluorescein isothiocyanate (FITC) R-phycoerythrin (PE) or biotin (Molecular Probes) the latter detected with PE-streptavidin (Caltag). Viable [excluding propidium iodide (PI)] CD4 + 8 + thymocytes and B220 + /surface (s)IgM − /sIgD − /CD43 − pre-B cells were purified in a FACStar+ or a modified FACS II cell sorter (Becton-Dickinson).
Supported by fellowships and grants from the ARC (P.B.) the Leukemia Society of America (A.S. and D.C.S.H.) the Cancer Research Institute the National Health and Medical Research Council (Reg. Key 973002) the National Cancer Institute (CA43540 and CA80188) the Josef Steiner Cancer Foundation and the Anti-Cancer Council of Victoria. We are grateful to S. Cory and L. Harrison for helpful discussions to G. Rudy for statistical advice and to J. Birtles for the manuscript preparation. We thank A. Harris S. Cory S. Bath K. Newton and L. O'Reilly for gifts of transgenic mice and Bim-specific monoclonal antibodies; A. Naughton E. Shomali and T. Gibbs for animal husbandry; J. Melny and R. Czajko for performing serum analyses; F. Battye D. Kaminaris V. Lapatis and J. Parker for operating the cell sorters; and L. Barnett L-C. Zhang S. Mifsud L. DiRago J. Beaumont S. Novakovic and A. Light for expert technical assistance.

Dates

Type	When
Created	23 years ago (July 27, 2002, 5:45 a.m.)
Deposited	8 months, 2 weeks ago (Dec. 8, 2024, 1:51 p.m.)
Indexed	4 days, 15 hours ago (Aug. 21, 2025, 12:31 p.m.)
Issued	25 years, 9 months ago (Nov. 26, 1999)
Published	25 years, 9 months ago (Nov. 26, 1999)
Published Print	25 years, 9 months ago (Nov. 26, 1999)

Funders 0

None

BibTeX

@article{Bouillet_1999, title={Proapoptotic Bcl-2 Relative Bim Required for Certain Apoptotic Responses, Leukocyte Homeostasis, and to Preclude Autoimmunity}, volume={286}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.286.5445.1735}, DOI={10.1126/science.286.5445.1735}, number={5445}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Bouillet, Philippe and Metcalf, Donald and Huang, David C. S. and Tarlinton, David M. and Kay, Tom W. H. and Köntgen, Frank and Adams, Jerry M. and Strasser, Andreas}, year={1999}, month=nov, pages={1735–1738} }

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      "unstructured": "Supported by fellowships and grants from the ARC (P.B.) the Leukemia Society of America (A.S. and D.C.S.H.) the Cancer Research Institute the National Health and Medical Research Council (Reg. Key 973002) the National Cancer Institute (CA43540 and CA80188) the Josef Steiner Cancer Foundation and the Anti-Cancer Council of Victoria. We are grateful to S. Cory and L. Harrison for helpful discussions to G. Rudy for statistical advice and to J. Birtles for the manuscript preparation. We thank A. Harris S. Cory S. Bath K. Newton and L. O'Reilly for gifts of transgenic mice and Bim-specific monoclonal antibodies; A. Naughton E. Shomali and T. Gibbs for animal husbandry; J. Melny and R. Czajko for performing serum analyses; F. Battye D. Kaminaris V. Lapatis and J. Parker for operating the cell sorters; and L. Barnett L-C. Zhang S. Mifsud L. DiRago J. Beaumont S. Novakovic and A. Light for expert technical assistance."
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