期刊
ONCOGENE
卷 33, 期 44, 页码 5221-5224出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.469
关键词
GSK-3; MCL-1; E mu-Myc; lymphoma; apoptosis
资金
- Deutsche Forschungsgemeinschaft [Ma 1967/1, Ma 1967/2]
- Deutsche Krebshilfe [109199, 107397]
- Spemann Graduate School of Biology and Medicine (SGBM) - Excellence Initiative of the German Federal and State Governments, Germany [GSC-4]
- Centre for Biological Signalling Studies (BIOSS) - Excellence Initiative, Germany [EXC-294]
- Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 23510] Funding Source: researchfish
The antiapoptotic BCL-2 protein MCL-1, which opposes mitochondrial outer membrane permeabilization, was shown to have a crucial role in the survival of hematopoietic cells. We have previously shown that, upon loss of phosphatidylinositol 3-kinase signaling, S159 of MCL-1 is phosphorylated by glycogen synthase kinase-3 (GSK-3), earmarking MCL-1 for enhanced ubiquitylation and degradation. In this study, we introduced MCL-1(wt) or the phosphorylation-deficient mutant MCL-1(S159A) in mouse BM cells, followed by adoptive transfer to recipient mice. Mice expressing MCL-1(S159A) exhibited significantly elevated white blood cell and lymphocyte counts, whereas no effect was observed on the distribution of T and B lymphocyte subsets or the numbers of monocytes, red blood cells or platelets. Expression of MCL-1(S159A) in E mu-Myc transgenic bone marrow significantly accelerated the onset of disease, and these mice displayed increased spleen weights compared with E mu-Myc/MCL-1(wt) mice. Our data demonstrate that the absence of MCL-1 S159 phosphorylation provides a survival advantage for hematopoietic cells in vivo and facilitates oncogenesis.
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