Mechanistic investigations of transcriptional regulation by bZIP transcription factors

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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.