Novel regulation of the p53 pathway through lipid metabolism and signalling

P53肿瘤抑制基因是与癌症有关的最著名的基因之一。它的正常细胞功能是通过阻止细胞分裂和激活应激反应通路来响应细胞应激。最典型的例子是当DNA受损时：p53通过停止细胞分裂和激活DNA修复程序来回应。由于癌症通常是由DNA损伤引起的，P53在预防癌症中起着关键作用，由于它在DNA修复中的作用，它经常被称为“基因组的守护者”。P53应对的压力之一是癌基因的激活--正常的细胞基因已经被改变，从而促进了癌症的发生。癌基因激活如何导致P53激活尚不清楚，但了解这一过程可能有助于我们设计提高P53激活(从而预防癌症)的治疗方法。值得注意的是，尽管P53在超过一半的癌症中是失活的，但许多癌症中仍然存在正常的P53。由于我们之前的一些研究，我们怀疑癌基因的激活可能会导致细胞代谢的压力(例如，向癌细胞提供足够的能量或营养)。我们研究了广泛的代谢基因，以确定它们是否可以在癌基因MYC激活时介导P53的激活。我们发现，与脂质神经酰胺的产生有关的几个基因对P53的激活是重要的。这一意想不到但非常引人注目的结果，加上随后实验的一些结果，导致了这项拨款申请。我们希望了解癌基因myc如何激活神经酰胺合成，进而神经酰胺合成如何激活p53。我们认为，这项研究将使我们和其他人能够设计新的治疗方法来激活肿瘤中的p53通路。特别是，我们将在侵袭性B细胞淋巴瘤(双重打击B细胞淋巴瘤)的一种亚型中检查这一途径，在这种亚型中经常发现正常的P53。我们将尝试增加神经酰胺的产生，以及神经酰胺在这些淋巴瘤中的作用方式和位置，看看我们是否可以激活P53来减少它们的生长和分裂。综上所述，我们希望揭示P53激活的一种新模式的分子机制，并针对这些机制来减少侵袭性B细胞淋巴瘤的生长。

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.