MCL1 is an anti-apoptotic member of the BCL-2 family that can be rapidly upregulated and a PEST protein that can be rapidly turned over. MCL1 is normally expressed at specific stages of differentiation and in response to specific stimuli. MCL1 transgenic mice have a high probability of developing massive lymph node hyperplasia with long latency leading to malignant lymphoma with high probability. Preliminary data indicate that MCL1 is subject to three post-translational modifications including two differing types of phosphorylation seen in viable versus apoptosing cells. The MCL1 phosphorylation seen in viable cells is not associated with a change in electrophoretic mobility; in contrast, the MCL1 phosphorylation seen in cells exposed to certain apoptosis-inducing agents is associated with a distinct change in mobility. MCL1 also undergoes a separate third modification that involves the loss of a segment at the N-terminus. This proposal focuses on these three modifications and on their impact on the anti-apoptotic activity of MCL1 and on the tumorigenesis seen in the MCL1 transgenic mice. BCL2 phosphorylation has been variously reported to enhance or to inhibit its anti-apoptotic function, and the fact that MCL1 phosphorylation differs in viable versus apoptosing cells may lend insight into this issue. Given this background, the investigator plans to: determine how specific post-translation modifications (i.e., phosphorylation; n-terminal modifications) affects turnover and the anti-apoptotic activity of MCL1. These studies will be complemented by in vivo assessment of the importance of these modifications, utilizing the transgenic system, which the investigator has developed.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Hematology Subcommittee 2 (HEM)
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Mccarthy, Susan A
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Dartmouth College
Schools of Medicine
United States
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Gui, Jingang; Hu, Zhuting; Tsai, Ching-Yi et al. (2015) MCL1 enhances the survival of CD8+ memory T Cells after viral infection. J Virol 89:2405-14
Nifoussi, Shanna K; Ratcliffe, Nora R; Ornstein, Deborah L et al. (2014) Inhibition of protein phosphatase 2A (PP2A) prevents Mcl-1 protein dephosphorylation at the Thr-163/Ser-159 phosphodegron, dramatically reducing expression in Mcl-1-amplified lymphoma cells. J Biol Chem 289:21950-9
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Michels, Jorg; O'Neill, Jason W; Dallman, Claire L et al. (2004) Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene 23:4818-27

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