Posttranslational regulation of Bim by caspase-3.
Bim is a proapoptotic BH3-domain-only member of the Bcl-2 family, and its expression is regulated both transcriptionally and posttranslationally. We developed an in vitro system examining the posttranslational regulation of Bim. Since Bim is a strong mediator of apoptosis, it has been quite difficult to establish cell lines stably overexpressing Bim. Coexpression of Bcl-2 enabled us to obtain mouse embryonic fibroblasts (MEFs) in which Bim is overexpressed and Bcl-2 expression is regulated by Tet-off system. Reduction of Bcl-2 levels by doxycycline treatment induced caspase-3 and caspase-7 activation, which was followed by Bim degradation. Bim degradation was suppressed by gene knockdown of caspase-3, but not by caspase-7 knockdown. The same posttranslational regulation of Bim was observed in osteoclasts. These results suggest that caspase-3 negatively regulates Bim expression by stimulating its degradation, thus creating a negative feedback loop in the Bim-caspase axis.
Wakeyama
Hidetoshi
H
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Akiyama
Toru
T
Kadono
Yuho
Y
Nakamura
Masaki
M
Oshima
Yasushi
Y
Nakamura
Kozo
K
Tanaka
Sakae
S
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053148:Caspase 3