Growth factors (e.g. EGF, FGF, PDGF, VEGF) and associated receptor tyrosine kinases (RTKs) regulate key signal transduction pathways which are frequently dysregulated in cancer. RTK pathways are common targets in chemotherapy drug development, but optimal patient selection and drug efficacy is often limited by lack of target specificity.
Colorectal cancer, one of the most common cancers in the UK, is treated by a multi-disciplinary team, combining expertise in surgery, chemotherapy and radiotherapy.
Background and Aims: Cells need to migrate away from their microenvironment to enable the tumour to metastasise. The growth factors Epidermal Growth Factor (EGF) and Transforming Growth Factor α (TGFα) stimulate the migration of fibroblasts into 3D collagen gels. Experiments using a number of growth factors concluded that some stimulated Akt phosphorylation whilst others reduced the phosphorylation of this pathway, but all stimulated migration; suggesting that multiple pathways are important for cell motility.
Project Background: The growth factor VEGF and a signal transduction pathway protein, Akt, may have an important role in oral tumours. Oral cancer patients from Dundee have been shown to have an increased expression of VEGF both in their tissue and in their serum. It has also been reported that Akt is activated in response to growth factors and this activation may be blocked by inhibitors.
Signalling through the classical Ras/ERK MAP kinase pathway is implicated in the genesis and progression of human tumours carrying activating mutations is upstream pathway effectors such as receptor tyrosine kinases and the Ras family of cellular proto-oncogenes.
Background: Two principle surveillance mechanisms have evolved to guard against errors during chromosome segregation. The mitotic checkpoint delays mitosis until each and every sister chromatid has achieved stable attachment to spindle microtubules (via a protein complex known as the kinetochore), and the microtubule error-correction pathway guides this attachment process by ensuring it remains free of errors. In spite of these safeguards, the majority of tumours still manage to continually missegregate their genome.
The DNA Damage Response (DDR) is a major component of a cells defence against disease. It serves to recognize and repair DNA damage, to regulate cell-cycle progression and where necessary, promote programmed cell death. One of the most potentially dangerous forms of DNA damage is a double stranded DNA break (DSB), which must be dealt with to maintain the structural and genetic integrity of a cell. Failure to do so results in generation of chromosomal aberrations such as chromosomal translocations that are potentially tumorigenic.
We have an interest in the targeting the ubiquitin-proteasome system for cancer therapy [1-4]. Regulation of the stability, activity and localization of proteins through ubiquitination is critical in the control of many fundamental processes of relevance to cancer and its therapy including: DNA
We demonstrated that the p53 tumour suppressor gene expresses at least twelve different p53 proteins due to alternative splicing, alternative initiation of translation and alternative promoter usage. We determined that p53 isoform proteins are expressed in normal human tissue in a tissue dependent manner. P53 isoforms are abnormally expressed in a wide range of cancer and are associated with breast cancer prognosis.