Loss of genetic material from chromosome 3p21.3 is one of the most common and earliest identified events in the pathogenesis of human solid tumors. The chromosomal area 3p2l.3 is thought to harbor at least one important tumor suppressor gene. In preliminary studies, we have identified and cloned a new gene from the common homozygous deletion area at 3p2l.3 and found that this gene is epigenetically inactivated in a large percentage of human lung cancers and breast cancers. The gene, named RASSF1A (Ras Association Domain Family 1A), has homology to the mammalian Ras effector Nore1. Our hypothesis is that RASSF1A is the tumor suppressor gene on 3p21.3. We will define the role of RASSF1A in the pathogenesis of human cancers by searching for aberrations of the gene (primarily epigenetic) in different types of cancer. We will prepare selective mouse knockouts of the two major alternative transcripts originating from the RASSF1 locus, with a focus on RASSF1A, which is inactivated in tumors. We will determine whether mice with heterozygous or homozygous deletions of this gene develop tumors. The homology of the RASSF1A gene with the mammalian Ras effector Nore1 suggests that the gene product may function in signal transduction pathways involving Raslike proteins. We will search for protein binding partners, including downstream targets, by using a series of defined Ras family proteins and yeast two-hybrid screens. The effect of RASSF1 expression on RAS signaling pathways will be studied. We will examine if RASSF1A, alone or in combination with activated RAS, induces cell death (apoptosis).
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