Project ID CM-HD2024_33


Co Supervisor 1A Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Host-Microbiome InteractionsWebsite

Co Supervisor 1B Faculty of Natural, Mathematical & Engineering Sciences, Chemistry, Muller GroupWebsite

Additional Supervisor Prof Sarah Pinder

Dissecting the mechanism of a viral anticancer protein

Apoptin is a small viral protein capable of inducing cell death selectively in cancer cells. Using a combination of protein semisynthesis and cell biological assays, we have collaboratively shown that Apoptin becomes phosphorylated in cancer cells, which activates the apoptin to disrupt the cytoskeleton and thereby promote cell death. This project builds on our discovery of apoptin’s mode of action and aims to fill in the mechanistic details using a multidisciplinary approach.

The key aims of the project are to fully identify the set of kinases that activate apoptin (Year 1), to chemically synthesise phosphorylated and/or fluorescently-labelled apoptin derivatives (Year 2) to delineate how phosphoApoptin interacts with the cytoskeleton through a multi-pronged cellular, biochemical and computational approach (Year 3). Finally, the project will explore whether the unique mechanism of apoptin activation allows transmission of phosphoApoptin, generated in cancer cells, to nearby bystander cells in a 3D tumour model (Year 4).

Summary and Outlook: Collectively, this project will provide mechanistic insights into how an anticancer protein selectively disrupts the cytoskeleton in its phosphorylated form, a development that would likely lead to a high impact publication. The resulting insights will provide a starting point for the design of next-generation anticancer peptides and proteins.

This project would suit candidates with a background in protein chemistry or cell biology and with a keen interest in acquiring interdisciplinary research skills at the interface of chemistry and biology. This project combines approaches across traditional scientific disciplines, building on the joint expertise of the supervisory team. The student will receive hands-on training in cell/cancer biology (Tavassoli lab), protein chemistry (Müller lab) and Molecular Dynamics (MD) simulations (Ulmschneider lab).

Representative Publications

M Flinterman, F Farzaneh, N Habib, F Malik, J Gäken and M Tavassoli. (2009) Delivery of Therapeutic Proteins as Secretable TAT Fusion Products. Molecular Therapy 17, 334. L Guelen, H Paterson, J Gäken, M Meyers, F Farzaneh, M Tavassoli. (2004) TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells. Oncogene 23, 1153. J Bullenkamp, J Gäken, F Festy, EZ Chong, T Ng, M Tavassoli. (2015) Apoptin interacts with and regulates the activity of protein kinase C beta in cancer cells. Apoptosis 20, 831.
J Wyatt, MM Müller, M Tavassoli. (2019) Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death. Cancers 11, 1975. Wyatt J, Chan YK, Hess M, Tavassoli M*, Müller MM*. Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse. Chem Sci 14, 3881 (2023). Margiola S1, Gerecht K1, Müller MM*. Semisynthetic ‘designer’p53 sheds light on a phosphorylation–acetylation relay. Chem Sci 12, 8563 (2021).