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，但类型可能非常不同，例如红细胞、神经元、肝细胞。这是由于转录过程，在这个过程中，我们决定哪些基因真正被阅读并翻译成活性的生物分子，即蛋白质。为了让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受到错误调控，就可能导致疾病。我的研究调查了转录是如何在我们的细胞内调节的，目的是提供应对此类疾病的策略。被称为转录因子的蛋白质通过与DNA上的特定位置(靠近它们控制的基因)结合来启动转录。这会导致其余的转录机制组装成一个巨大的蛋白质复合体，并复制基因，然后被翻译成蛋白质。如果特定的转录因子发生突变，或者在细胞内以错误的数量存在，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。我有兴趣了解CREB是如何控制转录的，以及我们是否可以利用这一知识来建议干预癌细胞中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，因为它们有明确的个体形状，所以被认为能够在细胞内执行各自的工作。相反，CREB的无序本质被推定为发挥功能作用。我将回答的主要问题是，这个角色是什么，如果CREB变得不那么无序，对细胞的正常工作会产生什么后果。特别是，我将发现无序是否有助于像CREB这样的转录因子在细胞核内的数十亿个碱基中找到它们的特定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自然DNA位点结合的类似蛋白质的小分子。这些分子会阻止转录因子的结合，从而改变细胞中产生的蛋白质。这些方法可以为创造治疗癌症的药物提供强有力的基础。

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.