HUMAN TREFOIL PEPTIDES - GENOMIC STRUCTURE IN 21Q22.3 AND COORDINATEDEXPRESSION

Trefoil peptides are small secretory proteins characterized by three i ntrachain disulfide bonds forming the trefoil motif or P-domain. They are abundantly expressed on mucosal surfaces, especially of the gastro intestinal tract. In pathological conditions such as ulcers, metaplasi a and neoplasia, their expression is upregulated. Three human trefoil peptides have been described: the estrogen-inducible pS2 protein, the spasmolytic protein and the intestinal trefoil factor. Recently, their role in the maintenance of surface integrity and ulcer healing was di scussed. We already mapped the corresponding three genes (BCEI, SML1, TFF3) to the same genomic region (21q22.3). In this paper, we show tha t the three genes are clustered in a tandemly orientated fashion withi n 50 kb on a bacterial artificial chromosome (BAG) recombinant. This c luster is located adjacent to D21S19 and the locus order is cen-D21S21 2-TFF3-SML1-BCEI-D21S19-tel, whereas transcription of all three genes is directed towards the centromere. The gene structure of SML1 exhibit s four exons, two of which encode the two separate trefoil motifs. TFF 3 and BCEI, both containing one trefoil motif, are composed of three e xons each, suggesting gene duplication and exon-shuffling events durin g evolution. The 5'- flanking region of SML1 was compared to the corre sponding region of other trefoil genes. Two motifs with identical sequ ence and positions are shared between SML1 and BCEI, thus presenting p ossible targets for stomach-specific gene regulation. Two other motifs are shared within all known human and rat trefoil genes, suggesting a coordinated regulation and/or a common locus-controlling region. Usin g RT-PCR, a change in the pattern of trefoil gene expression is detect ed in tissue samples from normal gastric mucosa, hyperplastic polyps, gastric cancer: and gastric cancer cell lines, respectively.