Clark, O.R.; (2011) The role of protein tyrosine phosphatases in neuroblastoma. Doctoral thesis , UCL (University College London).

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Abstract

Reversible phosphorylation of tyrosine residues on proteins is a cornerstone of cell to cell signalling, and is achieved through the concerted action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), which catalyse the addition and removal of phosphate moieties respectively. While the contribution of PTKs to oncogenesis and tumour maintenance has been well documented in a range of human cancers, knowledge of the specific role of PTPs has generally lagged behind. This thesis examines that role in neuroblastoma, a common and deadly sympathoadrenal tumour of infancy. We provide evidence that vanadium-­‐based PTP inhibitors cause synergistic hyperactivation of Akt and Erk, which drives an irreversible differentiation and senescence program that is independent of p53, p16INK4A and PTEN. It is then shown that in another group of tumour cell lines, such compounds used alone can induce selective caspase-­dependent, p53-independent apoptosis that is associated with activation of Akt and altered redox homeostasis. Lastly we examine the expression profile of the PTPome in a wide panel of neuroblastoma cell lines, providing preliminary evidence for candidate PTP oncogenes and tumour suppressors, as well as mediators of the effects of vanadium compounds.

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