Molecular characterization of the MIER2 and MIER3 transcriptional regulatory complexes

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When a cell receives an external stimulus or signal, it produces a response by altering the expression of specific set of genes. Some genes are activated, some are shut off, and all of this must be precisely coordinated in order to produce the proper response, whether it be to grow, to migrate or produce a hormone. The question is: how does this occur? My approach to answer this question began with studying how cells respond to fibroblast growth factor (FGF). FGF is a natural signal in the body and interestingly, it stimulates adult cells to proliferate but stimulates cells of an embryo to stop growing and become a specialized tissue, like muscle. My study of the cell's response to FGF, led to the discovery of a novel regulatory gene, called mier1, and the protein produced by this gene, MIER1, can control the expression of other genes. It can shut off genes required for a cell to proliferate and it can affect genes required for proper development of the embryo. Over the years, we have learned a lot about how MIER1 works at the molecular level. It acts like a hub to recruit other proteins to specific sites in the genome to form a large regulatory complex that functions to control expression of sets of genes. When the human genome was sequenced and analyzed, two other genes closely related to mier1 were identified: mier2 and mier3. My lab is the main lab in the world studying the two proteins, MIER2 and MIER3, encoded by these genes. Our evidence so far indicates that MIER2 and MIER3 can also recruit other proteins and form a complex that functions to control genes required for a cell to respond to a signal. However, their mode of action is distinct from the MIER1 complex and from each other. The goal of the research in this proposal is to characterize the MIER2 and MIER3 complexes and determine how they work. By doing so, we will obtain fundamental information about how the expression of groups of genes is synchronized to produce a very specific and unique cellular response. Ultimately, this would enable us to learn how to control cell behaviour.