Foxo-mediated Bim transcription is dispensable for the apoptosis of hematopoietic cells that is mediated by this BH3-only protein.
The BH3-only protein Bim is a critical initiator of apoptosis in hematopoietic cells. Bim is upregulated in response to growth factor withdrawal and in vitro studies have implicated the transcription factor Foxo3a as a critical inducer. To test the importance of this regulation in vivo, we generated mice with mutated Foxo-binding sites within the Bim promoters (Bim(ΔFoxo/ΔFoxo)). Contrary to Bim-deficient mice, Bim(ΔFoxo/ΔFoxo) mice had a normal hematopoietic system. Moreover, cytokine-dependent haematopoietic cells from Bim(ΔFoxo/ΔFoxo) and wt mice died at similar rates. These results indicate that regulation of Bim by Foxo transcription factors is not critical for the killing of hematopoietic cells.
1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.
Marco J
MJ
Herold
Leona
L
Rohrbeck
Mathias J
MJ
Lang
Raelene
R
Grumont
Steve
S
Gerondakis
Lin
L
Tai
Philippe
P
Bouillet
Thomas
T
Kaufmann
Andreas
A
Strasser
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000187:drug effects; D006413:Hematopoietic System / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc