Essential roles of MEK-1 in cells and mice

The proposed project aims at defining the essential functions of the MEK-1 protein. MEK-1 plays a central role in transducing various signals from the cell surface to intracellular signalling networks. It has been implicated in a variety of biological processes, such as proliferation, differentiation and cell death. Mutations which alter the activity of MEK (and its direct target ERK) play a role in the pathogenesis of severe diseases that affect large portions of the population. Specifically, the MEK/ERK pathway is deregulated in more than 30% of common cancers (lung, ovarian, pancreas, kidney, and colon). Thus, MEK-1 is considered an attractive therapeutic target, and major efforts are being made to design and test specific MEK inhibitors. An orally active MEK inhibitor has been presented recently that efficiently inhibits the growth of colon carcinomas in mice. The physiological role of MEK-1 in the context of the whole organism, however, is still unclear. To identify the physiological functions of MEK-1, and to gain insight into its suggested central role in the transduction of growth and survival signals, we will analyze MEK-1 deficient mice. We have recently generated MEK-1 knock out mice, in which the gene encoding for MEK-1 has been deleted. Because of the essential functions of MEK-1, MEK-1 deficient embryos mice do not survive until birth but already die in utero. We will analyse the cause of their death and generate cell lines from these embryos to analyse their behaviour with regard to proliferation, cell death and tranformation. Moreover, to circumvent embryonic lethality, we will generate mice in which MEK-1 can be knocked out either at on demand (at specific timepoints of development), or in which MEK-1 is knocked out in specific organs (brain, skin). The analysis of these mice should help us to understand the function of MEK-1 in the context of the whole organism. For example, mice without MEK-1 in the brain will be used to analyse the role of MEK-1 in ischemia, and mice without MEK-1 in the skin will serve as a tumor model for skin carcinogenesis. With these mouse lines, we hope to get inside into the function of MEK-1 in the transduction of growth and survival signals and in the pathogenesis of severe diseases such as cancer.