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.
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