Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction.
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.
Erlacher
Miriam
M
Division of Developmental Immunology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria.
Labi
Verena
V
Manzl
Claudia
C
Böck
Günther
G
Tzankov
Alexandar
A
Häcker
Georg
G
Michalak
Ewa
E
Strasser
Andreas
A
Villunger
Andreas
A
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001323:Autoantibodies / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007106:Immune Sera / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D007106:Immune Sera; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins