Regulation of apoptosis by MCL-1 phosphorylation in hematopoiesis and lymphoma
Final Report Abstract
MCL1 is required for survival of T and B lymphocytes and has also been shown to maintain hematopoietic stem cell survival. We previously showed that MCL1 is phosphorylated by GSK3, resulting in loss of MCL1 mediated protection from apoptosis. The GSK3 phosphorylation mutant, MCL1-S159A, exhibited a delay in apoptosis upon growth factor withdrawal. In this study, we compared the protective activity of MCL1-WT versus phosphorylation deficient MCL1-S159A in vivo, employing adoptive transfer of bone marrow (BM) cells, retrovirally transduced with MCL1-WT or MCL1-S159A in an IRES-GFP cassette. Equal numbers of BM cells expressing MCL1-WT or MCL1-S159A were transferred into irradiated recipient mice. Peripheral blood, BM, thymus, spleen and lymph node cells were analysed after 4 and 6 weeks, respectively. In peripheral blood, the proportion of neutrophil granulocytes, lymphocytes, monocytes, eosinophil granulocytes and basophil granulocytes did not differ in mice expressing MCL1-WT compared to those expressing MCL1-S159A. The distribution of thymocyte subpopulations, as well as the T and B cell populations in spleen and lymph nodes, remained unchanged upon expression of MCL1-WT vs. MCL1-S159A. However, the total amount of white blood cells (WBC) was elevated in mice expressing MCL1-S159A. As it has been shown that elevated WBC is indicative for increased survival conferred by antiapoptotic proteins like BCL-2 or MCL-1, we are currently investigating, by introducing of MCL1-WT vs. MCL1-S159A in BM cells from Eµ-myc mice, whether MCL1S159A cooperates with myc to induced lymphoma in an accelerated manner.
Publications
- Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53. Mol Cell, Volume 42, Issue 5, 10 June 2011, Pages 584-596
Céline Charvet, Manuela Wissler, Prisca Brauns-Schubert, Shang-Jui Wang, Yi Tang, Florian C. Sigloch, Hestia Mellert, Martin Brandenburg, Silke E. Lindner, Bernhard Breit, Douglas R. Green, Steven B. McMahon, Christoph Borner, Wei Gu and Ulrich Maurer
(See online at https://doi.org/10.1016/j.molcel.2011.03.033) - The role of MCL-1 phosphorylation for in vivo lymphocyte development, EMBO Molecular Medicine Workshop 2011 “Cell Death & Disease”, Obergurgl, Austria; 1st Price for best poster presentation
Silke E Lindner, Manuela Wissler, Albert Gründer, Martin Brandenburg, Christoph Borner, Céline Charvet and Ulrich Maurer
