期刊
CELL DEATH AND DIFFERENTIATION
卷 19, 期 6, 页码 1060-1068出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.198
关键词
Bcl-2 family; Bim; ERK-mediated phosphorylation; isoforms
资金
- Australian NHMRC [461221, 361646]
- Cancer Council Victoria
- Leukemia and Lymphoma Society (Specialized Center of Research) [7015]
- French Association pour la Recherche contre le Cancer
- INSERM/NHMRC
- Australian Research Council
- Viertel Charitable Foundation
The pro-apoptotic BH3-only protein Bim has a major role in hematopoietic homeostasis, particularly in the lymphocyte compartment, where it strongly affects immune function. The three major Bim isoforms (Bim(EL), Bim(L) and Bim(S)) are generated by alternative splicing. Bim(EL), the most abundant isoform, contains a unique sequence that has been reported to be the target of phosphorylation by several MAP kinases. In particular, Erk1/2 has been shown to interact with Bim(EL) through the DEF2 domain of Bim(EL) and specifically phosphorylate this isoform, thereby targeting it for ubiquitination and proteasomal degradation. To examine the physiological importance of this mechanism of regulation and of the alternative splicing of Bim, we have generated several Bim knock-in mouse strains and analyzed their hematopoietic system. Although mutation in the DEF2 domain reduces Bim(EL) degradation in some circumstances, this mutation did not significantly increase Bim's pro-apoptotic activity in vivo nor impact on the homeostasis of the hematopoietic system. We also show that Bim(EL) and Bim(L) are interchangeable, and that Bim(S) is dispensable for the function of Bim. Hence, we conclude that physiological regulation of Bim relies on mechanisms independent of its alternative splicing or the Erk-dependent phosphorylation of Bim(EL). Cell Death and Differentiation (2012) 19, 1060-1068; doi:10.1038/cdd.2011.198; published online 13 January 2012
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