Mechanistic investigations of transcriptional regulation by bZIP transcription factors

我们体内的细胞都以DNA的形式包含相同的遗传信息，但在类型上可能非常不同，例如红细胞、神经元、肝细胞。这是由于转录的过程，在这个过程中，决定我们的哪些基因被读取并翻译成活跃的生物分子；的蛋白质。为了使细胞正常发育并保持健康，在正确的时间以正确的数量制造正确的蛋白质是很重要的。如果转录过程在某种程度上被错误调控，那么就会导致疾病。我的研究调查了我们细胞内的转录是如何被调节的，目的是为治疗这些疾病的策略提供信息。被称为转录因子的蛋白质通过结合DNA上的特定位点（靠近它们控制的基因）开始转录。这导致转录机制的其余部分组装成一个巨大的蛋白质复合体，并产生基因的副本，然后被翻译成蛋白质。如果特定的转录因子发生突变，或者在细胞内出现错误的数量，那么这可能会给细胞带来问题。其中一种被称为CREB的转录因子在许多不同类型的癌细胞中含量升高。我感兴趣的是找出CREB如何控制转录，以及我们是否可以利用这些知识提出干预癌细胞中CREB功能的方法。像许多转录因子一样，CREB没有明确的形状；它是灵活的、波动的和无序的。这与大多数蛋白质不同，它们被认为能够在细胞内执行各自的任务，因为它们具有明确的个体形状。相反，CREB的无序性被认为发挥了功能性作用。我将讨论这个主要问题，即这个角色是什么，以及如果CREB的紊乱程度降低，对细胞的正常工作有什么影响。特别是，我将发现，紊乱是否有助于像CREB这样的转录因子在细胞核内数十亿个碱基中找到它们特定的DNA位点。我将利用这些信息来帮助设计和测试可以与转录因子的天然DNA位点结合的小蛋白质样分子。这些分子会阻止转录因子的结合，从而改变细胞中生成的蛋白质。这些方法可以为开发治疗癌症的药物提供坚实的基础。

The cells within our bodies all contain the same genetic information in the form of DNA but can be very different in type e.g. red blood cells, neurons, liver cells. This is due to the process of transcription, where decisions get made about which of our genes actually get read and translated into active biological molecules; the proteins. For cells to develop correctly and remain healthy, it is important that the correct proteins are made, in the correct amounts, and at the correct times. If the transcription process is misregulated in some way then this can lead to disease. My research investigates how transcription is regulated within our cells, with the aim of informing strategies for tackling such diseases.Proteins called transcription factors start transcription by binding to specific sites on the DNA (near to the genes that they control). This causes the rest of the transcriptional machinery to assemble into an enormous protein complex, and make a copy of the gene, that then gets translated to make a protein. If specific transcription factors are mutated, or present in the wrong amounts within the cell, then this can cause problems for the cell. One such transcription factor, called CREB, is found in elevated amounts in many different types of cancer cells. I am interested in finding out how CREB controls transcription, and whether we can use this knowledge to suggest ways of intervening with CREB function in cancer cells. CREB, like many transcription factors, does not have a well-defined shape; it is flexible, fluctuating and disordered. This is unlike most proteins, which are considered able to perform their individual jobs within the cell because of their well-defined individual shapes. Instead the disordered nature of CREB is presumed to play a functional role. I will be addressing the major question as to what this role is, and what the consequences are to the normal working of a cell if CREB is made less disordered. In particular I will be finding out if being disordered helps transcription factors like CREB find their specific DNA sites amongst the billions of bases within the cell nucleus. I will use this information to help design and test small protein-like molecules that can bind to the natural DNA sites of transcription factors. These molecules would block transcription factors binding, and therefore alter the proteins that get made in the cell. These sorts of approaches could provide a strong basis for creating drugs for cancer treatment.