Characterisation of Notch asparaginyl hydroxylation by FIH-1.

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Cells within our body receive numerous signals telling them when to grow, when to turn into another cell type and exactly what type, and even how to respond to situations like low oxygen. These signals and cells response are very important during embryonic development, when these signals cause a single cell to become a complete person, and also in adults. Here in the embryo, and also in adults, stem cells are very important because they can become many different kinds of cells, depending on what the body needs. When the signals don't work properly, they cause major problems and diseases, from birth defects, to cancer. Notch is an important protein involved in receiving and passing on certain signals, and is found in organisms as diverse as worms and humans. It tells cells, especially stem cells and other similar cells, when and how to change from one type of cell to another. For example, it is very important in the generation of many different types of blood cells from a single precursor cell. Notch has also been implicated in human diseases such as cancer, where signalling goes wrong and cells keep multiplying out of control, and also certain types of heart disease. Another protein, called FIH, is an oxygen sensor that signals to the cell when there is not enough oxygen around. FIH has also been implicated in cancer and heart disease. We have recently found evidence suggesting that FIH can also influence the activity of the Notch proteins. This means that oxygen levels can potentially have an effect on stem cells and other processes controlled by Notch, and may be very important in cancer and other diseases. This project will first confirm the connection between FIH and Notch. There are a number of different Notch proteins, so we will see if this connection works with all of them. It will also try and work out the consequence of this connection is and how important it is. Finally, the likely biological consequences on human diseases, specifically cancer.