The CDKN2A locus : mechanisms of tumour supression

• Main Author: Kallenberg, David Marc
• Published: St George's, University of London 2014
• Subjects: 616.99
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.656854

Malignant melanoma currently accounts for four percent of newly diagnosed cancers in the UK. The genetic alterations that bring about melanoma are not fully understood, but several genes and pathways have been implicated. Following oncogenic activation, somatic cells undergo an irreversible cessation of proliferation (senescence), which is thought to act as a barrier to malignancy. Oncogenic BRAF mutations (commonly BRAFv600E) are found in 50-70% of melanomas. Oncogene induced senescence is evident in benign melanocytic naevi, where BRAF mutations are often found with p 16 activity. P 16 is a tumour suppressor protein and senescence mediator often defective in melanoma. The aim of this project is to understand better the role that genetic alterations have in melanoma progression. Normal, p 16-null, and immortalised p 16-null human melanocytes were transfected with vectors that can be induced to express BRAFwT or BRAFv600E. My data suggest that low levels of BRAFvE may induce proliferation and support the hypothesis that p 16 is necessary for BRAF -induced senescence. It has now been illustrated that the proliferation rate of p 16-null melanocytes is below normal in culture and can be restored in the presence of keratinocytic growth factors (endothelin 1 and stem cell factor). Additionally, the dependency exhibited by pl6-null human melanocytes is reduced by inhibiting p53 or through immortalisation with TERT, which removes a source ofp53 signalling. The AKT signalling pathway has been shown to playa major role in mediating this response, suggesting that the keratinocyte factors signal through this pathway resulting in growth and survival. The role oftelomerase in the immortalisation of cells, through extending telomeres, has previously been well characterised. It was observed that cells immortalised with hTERT were less dependent on growth factors for survival. Further transformation assays have demonstrated that telomerase not only immortalises cells, but also transforms them altering many characteristics.