Dissertation
The role of PIM1 in cell survival
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2009
DOI:
https://doi.org/10.7273/000005647
Abstract
PIM1, a serine/threonine protein kinase, is a stress-induced kinase regulated by cytokines, growth factors, hormones, ischemia, hypoxia, heat shock and infective agents. It has functions in cell survival, proliferation and differentiation. However, the focus of this study is on its contribution to cell survival. Over-expression of PIM1 inhibits apoptosis and promotes cell survival in a variety of cells, including cytokine dependent hematopoietic cells, prostate cancer cells, cardiomyocytes, basophils and eosinophils. Until now, the only recognized proapoptotic target of PIM1 was BAD. BAD phosphorylation by PIM1 results in inhibition of its proapoptotic activity. Because PIM1 can be induced by stress, it was of interest to examine potential protein targets that are involved in the stress response. One such target found in this study is apoptosis signaling kinase-1, ASK1. This is the first time that PIM1 has been shown to be involved in the mitogen-activated kinase mediated cell survival pathway through phosphorylation and inactivation of ASK1. The significance of this event is that ASK1 inhibition results in the inhibition of the downstream targets JNK and p38 subsequently reducing caspase-3 activation and cell apoptosis. In addition, this study also provides evidence to show that PIM1 plays a larger role in cell survival than originally thought by functionally linking two of its previously identified substrates MDM2 and FOXO3a. PIM1 was found to promote cell survival through MDM2-mediated degradation of FOXO3a in H1299 cells. In conclusion, this research provides a mechanistic explanation for how PIM1 contributes to cell survival and as a result significantly extends the current understanding of this function of PIM1.
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Details
- Title
- The role of PIM1 in cell survival
- Creators
- Juan Gu
- Contributors
- Nancy S. Magnuson (Chair)Raymond Reeves (Committee Member) - Washington State University, School of Molecular BiosciencesMargaret Black (Committee Member) - Washington State University, School of Molecular BiosciencesPhilip Fowler Mixter (Committee Member) - Washington State University, School of Molecular Biosciences
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 112
- Identifiers
- 99901054534301842
- Language
- English
- Resource Type
- Dissertation