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Oncogene. 2014 Oct 30;33(44):5221-4. doi: 10.1038/onc.2013.469. Epub 2013 Nov 11.

Increased leukocyte survival and accelerated onset of lymphoma in the absence of MCL-1 S159-phosphorylation.

Author information

1
1] Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany [2] Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
2
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
3
Department of Molecular Hematology, Center for Clinical Research, University Hospital, Freiburg, Germany.
4
Institute of Pathology, University Medical Centre Freiburg, Freiburg, Germany.
5
Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria.
6
1] Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany [2] Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany [3] Spemann Graduate School for Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
7
1] Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany [2] Spemann Graduate School for Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany [3] BIOSS, Centre for Biological Signaling Studies, Freiburg, Germany.
8
Institut Cochin, INSERM U1016/CNRS UMR 8104, Université Paris Descartes, Rue Méchain, Paris.

Abstract

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 Eμ-Myc transgenic bone marrow significantly accelerated the onset of disease, and these mice displayed increased spleen weights compared with Eμ-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.

PMID:
24213575
PMCID:
PMC4155018
DOI:
10.1038/onc.2013.469
[Indexed for MEDLINE]
Free PMC Article

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