Assignment of WDR7 (alias TRAG, TGF-beta resistance associated gene) to orthologous regions of human chromosome 18q21.1-->q22 and mouse chromosome 18D.1-E.3 by fluorescence in situ hybridization.

Abstract

We have identified a new, large gene through its elevated expression in a TGF-ß resistant cell line, B5T. This line was derived from a TGF-ß sensitive rat liver epithelial line (RLE M13) following spontaneous transformation by repeated passaging. We have named the gene TRAG (TGF-ß resistance associated gene), but it has also been given the official symbol WDR7 (WD Repeat 7) due to the presence of two WD repeat elements (Smith et al., 1999) by the Human Gene Nomenclature Committee. Both the gene and protein will therefore henceforth be known as WDR7/TRAG. The coding sequence is large (4,398 base pairs) and apparently unique, as it does not match any known genes or gene products present in currently available databases. Limited amino acid homology exists between WDR7/TRAG protein and a putative Drosophila G-protein subunit (GenBank Accession Number AL021086). A cDNA clone from human brain does exist which shows high nucleotide homology with WDR7/TRAG (F87%; KIAA0541, GenBank Accession Number AB011113), but this clone has not been characterized or further investigated beyond its reporting (Nagase et al., 1998). WDR7/TRAG protein has been demonstrated to be greatly elevated in numerous malignant, transformed cell lines from both human and rat, and shows a striking correlation with both TGF-ß resistance and metastatic potential. High levels of WDR7/TRAG were also observed in primary mouse tumors from TGF-ß/c-myc transgenic mice (Sanders et al., manuscript in preparation). Using FISH analysis, WDR7/TRAG was localized to orthologous regions on mouse (18D.1–E.3) and human (18q21.1→q22) chromosomes. This region in humans, the long arm of chromosome 18, encompasses a number of important genes linked to the process of tumorigenesis, particularly that of colon and pancreatic cancer (Cho and Vogelstein, 1992; Hahn et al., 1996). The DCC (deleted in colon cancer), MADH4 (alias DPC4 deleted in pancreatic cancer, also known as SMAD4), and BCL2 genes all lie on 18q and have all been shown to play a role in a variety of cancers (Tsujimoto et al., 1985; Hedrick et al., 1994; Hahn et al., 1996). Loss or translocation of 18q is a prevalent chromosomal aberration found in a subset of human cancers (Jen et al., 1994). It remains to be demonstrated whether any relationship exists between WDR7/TRAG overexpression and 18q loss in the primary tumors and tumor cell lines examined thus far. Further characterization and determination of WDR7/TRAG function is currently underway.