Human N-benzoyl-l-tyrosyl-p-aminobenzoic acid hydrolase (human meprin): genomic structure of the α and β subunits

摘要

piN/i-Benzoyl-L-tyrosyl-ip/i-aminobenzoic acid hydrolase (PPH, human meprin), a zinc-metalloendopeptidase of the astacin family, consists of two similar subunits. As well as in small-intestinal epithelial cells, the enzyme is found in lamina propria leucocytes, human cancer cells and colorectal cancer tissue, making it a potential candidate for a role in tumour formation and cancer progression. To elucidate the mechanisms that control iPPH/i gene expression and to gain more insights into the evolutionary relationship of the two subunits, we analysed the complete exon-intron organization and searched for putative regulatory elements in 3 kb of the upstream region of both genes. The human gene for the α subunit is approx. 35 kb in size and contains 14 exons. The gene for the β subunit is organized in 15 exons and spans approx. 27 kb. A comparison of both genes indicates strong structural similarities. The exons are almost identical in size, except exon 13 in PPHα, which codes for an additional I domain not present in PPHβ. The locations of the respective exon-intron junctions and the intron phases are almost identical; five of them contain conserved split codons. The main variation is in the intron lengths. It can be concluded that PPHα and PPHβ are derived from a common ancestor. Sequence analysis of the 5? flanking DNA with a computer search for promoter elements and different promoter constructs transfected into Caco-2 cells revealed a number of potential regulatory motifs and suggests that each of the two genes is regulated independently./p