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  The Survivin Interactome in Health and Disease


   School of Life Sciences

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  Dr S Wheatley  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Survivin is a small protein that is essential for life but that also contributes to disease, most notably cancer, in which its abnormal overexpression is linked to therapeutic resistance and metastasis. However, it is also a prognostic marker in certain immune disorders, including rheumatoid arthritis and multiple sclerosis. While its essential role is directly attributed to its role within the chromosomal passenger complex, a heterotetrameric complex that ensures genetic stability is maintained in mitosis, and by interacting with myosin II, thereby coordinating chromosome segregation and cytokinesis, how its mitotic role contributes to its involvement in disease, remains unclear. A second, non-essential role of survivin is as an inhibitor of “apoptosis”, but exactly how it prevents cells from this programmed form if cell death, is also incompletely understood. Although survivin has received a lot of attention as an oncotherapeutic target, to date there has been little success in developing a survivin-specific drug. One of the reasons for this is its lack of enzymatic activity. However, more recently attention has begun to turn to protein-protein interactions for novel therapeutic avenues of exploration. This is where survivin comes back into the limelight.

The Wheatley lab has been investigating interactions between survivin and other proteins for many years. Its role in the chromosomal passenger complex is well documented, but the inventory of the survivin interactome keeps growing, and its involvement in multiple signalling pathways, is largely due to its ability to bind to and chaperone a variety of different proteins in different cellular compartment. It is found in the cytoplasm, on the mitotic chromosomes, in the nucleus of stressed cells, as well as in the mitochondria of transformed (cancerous) cells. In the Wheatley lab we use a range of techniques to investigate protein-protein interactions in human cells, from in vitro pull-down assays, to in vivo BiFC/advanced fluorescence imaging, and complement these assays with a variety of treatment regimes: exponential and mitotically synchronised cells, hypoxic, irradiated or insulted (apoptotic stimuli), normal and transformed cells. Future projects will all pertain to the “survivin interactome”, and investigate specific interactions in different subcellular compartments. The overall goal is to determine how these interactions contribute to human/ animal health, ageing and disease. As an example of project design, there are several transcription factors that are candidate interactors of survivin. Survivin would encounter these factors, when it relocates to the nucleus in hypoxia, or potentially in immune disorders.

We hypothesis that survivin-transcription factor(s) interactions may cause transcriptional reprogramming. Any interaction pursued in this project will be followed through to qPCR to assess changes in mRNA transcription of downstream factors, and protein expression analysis by immunoblotting. Alternatively, a similar project related to the mitochondria will combine the protein-protein interaction experiments with metabolic and apoptotic assays. The student will be encouraged to work on the area of the survivin interactome that most closely relates to their interests, from fundamentals of mitosis and apoptosis, through to cancer, arthritis or MS, and additional specialist supervisors will be selected accordingly to support the student. 

Biological Sciences (4)

References

• Wheatley, SP., Altieri, DC., Survivin at a Glance. J. Cell Sci., 2019, 132 (7)352019
• Townley, AR., and Wheatley, SP., Mitochondrial survivin reduces oxidative phosphorylation in cancer cells by inhibiting mitophagy J. Cell Sci. 2020;133(21)
• Survivin inhibits excessive autophagy in cancer cells but does so independently of its interaction with LC3. Humphry, NJ., and Wheatley, SP. Open Biology. 2018; 7, bio037374, 1-7.
• Dunajová, L., Cash, E., Markus, R., Rochette, S., Townley, AR., Wheatley, SP. The N-Terminus of Survivin is a Mitochondrial Targeting Sequence and C-Src Regulator. Cell Sci, 2016; 129:2707-2712.
• Aljaberi AM, Webster JR, Wheatley SP. Mitotic activity of survivin is regulated by acetylation at K129. Cell Cycle. 2015;14(11):1738-47

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