Novel regulation of the p53 pathway through lipid metabolism and signalling

点击翻译按钮获取中文摘要

The p53 tumour suppressor gene is one of the best known genes involved in cancer. Its normal cellular function is to respond to cellular stresses by stopping cells from dividing and activating stress response pathways. The best characterised example of this is when DNA is damaged: p53 responds by halting cell division and activating the DNA repair programme. Since cancer is often caused by damaged DNA, p53 plays a critical role in preventing cancer and, due to its role in DNA repair, it is often referred to as the 'Guardian of the Genome'. One of the stresses that p53 responds to is the activation of oncogenes - normal cellular genes that have been altered so that they promote cancer. How oncogene activation leads to p53 activation is unclear, but gaining an understanding of this process could help us to design therapies that increase p53 activation (and therefore protection from cancer). It is important to note that, although p53 is inactivated in more than half of cancers, there are still many cancers in which normal p53 is present.Due to some of our prior research, we suspected that oncogene activation may lead to stresses in cellular metabolism (e.g. sufficient supply of energy or nutrients to the cancer cells). We investigated a wide range of metabolic genes to see if they could mediate the activation of p53 upon activation of the oncogene MYC. We found that several genes involved in production of the lipid ceramide were important for the activation of p53. This unexpected but very striking result, plus some results from consequent experiments, have led to this grant proposal.We wish to understand how the oncogene MYC activated ceramide synthesis and, in turn, how ceramide synthesis activates p53. We propose that this research will enable us and others to design new therapies for activation of the p53 pathway in tumours. In particular, we will examine this pathway in a subtype of aggressive B cell lymphomas (double hit B cell lymphomas) in which normal p53 is often found. We will try to increase ceramide production and how and where ceramide functions in these lymphomas to see if we can activate p53 to reduce their growth and division.In summary, we wish to uncover the molecular mechanisms of a novel mode of activation of p53 and to target these mechanisms to reduce the growth of aggressive B cell lymphomas.