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¹ Division of Developmental Immunology and ² Division of Experimental Pathophysiology and Immunology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria
³ Institute of Pathology, University of Basel, CH-4051 Basel, Switzerland
⁴ Institute for Medical Microbiology, Technical University of Munich, 80290 Munich, Germany
⁵ The Walter and Eliza Hall Institute of Medical Research, Melbourne 3050, Australia
⁶ Department of Medical Biology, The University of Melbourne, Melbourne 3010, Australia

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

The physiological role of B cell lymphoma 2 (Bcl-2) homology 3–only proteins has been investigated in mice lacking the individual genes identifying rate-limiting roles for Bim (Bcl-2–interacting mediator of cell death) and Puma (p53–up-regulated modulator of apoptosis) in apoptosis induction. The loss of Bim protects lymphocytes from apoptosis induced by cytokine deprivation and deregulated Ca⁺⁺ flux and interferes with the deletion of autoreactive lymphocytes and the shutdown of immune responses. In contrast, Puma is considered the key mediator of p53-induced apoptosis. To investigate the hypothesis that Bim and Puma have overlapping functions, we generated mice lacking both genes and found that bim^–/–/puma^–/– animals develop multiple postnatal defects that are not observed in the single knockout mice. Most strikingly, hyperplasia of lymphatic organs is comparable with that observed in mice overexpressing Bcl-2 in all hemopoietic cells exceeding the hyperplasia observed in bim^–/– mice. Bim and Puma also have clearly overlapping functions in p53-dependent and -independent apoptosis. Their combined loss promotes spontaneous tumorigenesis, causing the malignancies observed in Bcl-2 transgenic mice, but does not exacerbate the autoimmunity observed in the absence of Bim.

M. Erlacher's present address is Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Hospital of Freiburg, 79104 Freiburg, Germany.

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