Grant: Operating Grant

There are a group of proteins present in all cells that are related to the founding member of the family, Bcl-2. Depending on which of the proteins are present in any given cell, their quantity, and their level of activity, they can control whether a cell continues to live, or whether it makes a decision to undergo suicide. Mcl-1 is a member of this family, but in addition to its role in promoting cell survival, it is well known to cause changes in the rate at which cells divide. By breaking Mcl-1 down into smaller fragments, and changing some parts of the protein, we can introduce the altered forms into cells to investigate the key features that controls this alternate activity. We have strong evidence that Mcl-1 acts as an important adaptor protein in the nucleus, close to the DNA molecules, and it can participate in the machinery that allows a cell to make the decision to divide into two daughter cells. We also have evidence that it functions when DNA is damaged by chemicals and it plays a role in telling the cells not to divide. Taken together, Mcl-1 may have several functions that could determine whether a cell may grow inappropriately and thus develop into cancer. We think that abnormal functioning of Mcl-1 may allow cells to divide when they should not, and could thus lead to build-up of abnormal cancerous cells. In future, a better understanding of Mcl-1's involvement in these processes may be useful in better understanding some aspects of cancer development. The knowledge gained from our studies will help us to understand many aspects of cell division, and it may be possible to utilize the new information to interrupt the abnormal processes, by designing drugs to disrupt Mcl-1 functions.