The Journal of Experimental Medicine
ThymUS '08
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Published online February 25, 2008
doi:10.1084/jem.20071658
The Journal of Experimental Medicine, Vol. 205, No. 3, 641-655
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Labi et al.
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ARTICLE

 Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates {gamma} irradiation–induced thymic lymphoma development

Verena Labi1, Miriam Erlacher1, Stephan Kiessling1, Claudia Manzl1, Anna Frenzel1, Lorraine O'Reilly2, Andreas Strasser2, and Andreas Villunger1

1 Division of Developmental Immunology, Biocenter, Innsbruck Medical University, 6020 Innsbruck, Austria
2 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia

CORRESPONDENCE Andreas Villunger: andreas.villunger{at}i-med.ac.at

Members of the Bcl-2 protein family play crucial roles in the maintenance of tissue homeostasis by regulating apoptosis in response to developmental cues or exogenous stress. Proapoptotic BH3-only members of the Bcl-2 family are essential for initiation of cell death, and they function by activating the proapoptotic Bcl-2 family members Bax and/or Bak, either directly or indirectly through binding to prosurvival Bcl-2 family members. Bax and Bak then elicit the downstream events in apoptosis signaling. Mammals have at least eight BH3-only proteins and they are activated in a stimulus-specific, as well as a cell type–specific, manner. We have generated mice lacking the BH3-only protein Bcl-2–modifying factor (Bmf) to investigate its role in cell death signaling. Our studies reveal that Bmf is dispensable for embryonic development and certain forms of stress-induced apoptosis, including loss of cell attachment (anoikis) or UV irradiation. Remarkably, loss of Bmf protected lymphocytes against apoptosis induced by glucocorticoids or histone deacetylase inhibition. Moreover, bmf–/– mice develop a B cell–restricted lymphadenopathy caused by the abnormal resistance of these cells to a range of apoptotic stimuli. Finally, Bmf-deficiency accelerated the development of {gamma} irradiation–induced thymic lymphomas. Our results demonstrate that Bmf plays a critical role in apoptosis signaling and can function as a tumor suppressor.

Abbreviations used: BCR, B cell receptor; BH, Bcl-2 homology; Bmf, Bcl-2–modifying factor; CBHA, m-carboxycinnamic acid bis-hydroxamide; DLC, dynein light chain; DN, double-negative; DP, double-positive; ES, embryonic stem; HDAC, histone deacetylase; MEF, mouse embryonic fibroblast; PI, propidium iodide; SAHA, suberoylanilide hydroxamic acid; SP, single-positive; TNF-R, tumor necrosis factor receptor.

A. Strasser and A. Villunger contributed equally to this paper.

M. Erlacher's present address is Dept. of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, 79104 Freiburg, Germany.


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