Genomic Organization of the HumanKAI1Metastasis-Suppressor Gene

Abstract

Decreased expression of the humanKAI1metastasis-suppressor gene is involved in the progression of human prostatic cancer and possibly lung and breast cancer. To evaluate the frequency of mutation and allelic loss during the progression of human cancer, as well as to determine the regulatory mechanism for the expression of theKAI1gene in normal and cancerous tissues, we characterized the 5′-promoter region, exon/intron organization, and transcription initiation site of the humanKAI1gene. About 80 kb of DNA was identified as the humanKAI1gene, which contains 8 kb of 5′-region, 10 exons, 9 introns, and 8 kb of DNA following exon 10. The coding region starts in exon 3 and ends in exon 10. The size of intron 1 is 29 kb, which almost equals the sizes of all other introns combined. A CpG island is present in the 5′-promoter region and extends to exon 1 and intron 1. The promoter region has no TATA or CCAAT box but has many putative binding motifs for various transcription factors, including nine Sp1 sites and five AP2 sites. These results suggest a diverse regulatory mechanism for the expression of theKAI1gene in human tissues. The transcription initiation site of theKAI1gene is located 181 bp upstream of the first nucleotide of the translation initiation codon. Comparisons of gene structures betweenKAI1and seven other members of the transmembrane 4 superfamily revealed that the splicing sites relative to the different structural domains of the predicted proteins are well conserved, suggesting that these genes are evolutionarily related and that they arose through gene duplication and divergent evolution.