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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA057359-13
Application #
6729212
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mccarthy, Susan A
Project Start
1992-06-01
Project End
2006-07-31
Budget Start
2004-04-01
Budget End
2006-07-31
Support Year
13
Fiscal Year
2004
Total Cost
$321,975
Indirect Cost
Name
Dartmouth College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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
Huang, Li-Hao; Gui, Jingang; Artinger, Erika et al. (2013) Acat1 gene ablation in mice increases hematopoietic progenitor cell proliferation in bone marrow and causes leukocytosis. Arterioscler Thromb Vasc Biol 33:2081-7
Nifoussi, Shanna K; Vrana, Julie A; Domina, Aaron M et al. (2012) Thr 163 phosphorylation causes Mcl-1 stabilization when degradation is independent of the adjacent GSK3-targeted phosphodegron, promoting drug resistance in cancer. PLoS One 7:e47060
Gui, Jingang; Morales, Amanda J; Maxey, Sophie E et al. (2011) MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood. Int Immunol 23:647-59
De Biasio, Alfredo; Vrana, Julie A; Zhou, Ping et al. (2007) N-terminal truncation of antiapoptotic MCL1, but not G2/M-induced phosphorylation, is associated with stabilization and abundant expression in tumor cells. J Biol Chem 282:23919-36
Kobayashi, Shogo; Lee, Sun-Hee; Meng, Xue W et al. (2007) Serine 64 phosphorylation enhances the antiapoptotic function of Mcl-1. J Biol Chem 282:18407-17
Marriott, Helen M; Bingle, Colin D; Read, Robert C et al. (2005) Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. J Clin Invest 115:359-68
Domina, Aaron M; Vrana, Julie A; Gregory, Mark A et al. (2004) MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene 23:5301-15
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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