We have been studying the transformation mechanisms of oncogenes that act through the Mitogen Activated Protein Kinase (MAPK) signaling pathway. DRM ( D own- R egulated by M os)/Gremlin is a Bone Morphogenetic Protein (BMP) antagonist, initially identified by our lab, which is expressed in a tissue-specific fashion in vivo. With the exception of primary fibroblasts and a few cell lines, most transformed cells in culture fail to express DRM/Gremlin, and we observed that its expression can be suppressed by oncogene transformation, via the MAPK pathway. We hypothesized this loss of expression may be important for the initiation or progression of specific tumors. Our recent work has focused on characterizing the properties DRM and analyzing its function and mechanism of action in transformed cells. Using somatic cell and radiation hybrid analysis we mapped DRM/Gremlin to human chromosome 15(q13-q15), a region whose deletion has been linked to breast, mesothelial and prostate malignancies. We also mapped the murine gene to a region of mouse chromosome 2 that contains markers found on human chromosome 15. RNA analysis indicated the gene was expressed primarily in human ovary, small intestine, colon, brain, and skeletal muscle. Analysis of RNA from different regions of the brain indicated increased levels in specific areas of the brain, and we detected expression in normal astrocytes and neurons in culture. Expression was detected in only one of ten brain tumor-derived lines tested. When retroviral and plasmid clones expressing DRM/Gremlin were reintroduced into these cells, some showed alterations in growth transformation-associated phenotypic characteristics. We are analyzing these responses, and, using RNA probes and antisera developed against purified bacterially expressed human DRM/Gremlin, we are performing in situ and immunohistochemical analysis to identify specific sites of DRM/Gremlin expression within positive human tissues.
