The role of raf-1 and mek-1 in cell proliferation, differentiation, and apoptosis examined by conditional gene inactivation

Cytosolic serinehreonine kinases of the Raf family play a central role in evolutionarily conserved signal transduction pathways. These enzymes have been implicated in a variety of biological processes, most notably in regulated and deregulated proliferation. because of the latter, they are considered attractive therapeutic targets. The current project started in August 2000 and was aimed at answering the still unresolved question of the physiological functions of the cellular oncogene Raf-1 in the context of the whole organism. To implement this goal, we constructed mice lacking the Raf-1 kinase in the whole organism or in selected tissues. The data obtained in this system have shown that Raf-1, despite the vast amount of literature portraying it as a transducer of proliferative signals, is in truth dispensable for proliferation in vivo and in vitro. Instead, the essential function of this protein consists in inhibiting the action of specific proteases that mediate programmed cell death as well as erythroid differentiation [(1-4). The discovery of this unsuspected essential function of the Raf-1 kinase has elicited a considerable amount of interest, documented by coverage of this work in several recent reviews/news features appeared in leading Journals in the field. The tools (animals, cell lines) produced during this two-year project are being used in a number of informal international collaborations as well as in the context of an EC Project (QLRT-CT-2000-02278 "Spatialemporal organization and regulation of the MAPK pathway").