The human alpha-fetoprotein gene. Sequence organization and the 5' flanking region.

Abstract

The human a-fetoprotein (AFP) gene was isolated into three overlapping clones in bacteriophage X vectors and its sequence organization analyzed by restriction endonuclease mapping and nucleotide sequencing.The human AFP gene is about 20 kilobase pairs long and contains 15 exons and 14 introns.The overall organization of the human AFP gene is similar to that of the mouse AFP gene, with all but two exons showing identical sizes.Nucleotide sequences at all exonlintron junctions display similarity to the consensus boundary sequence (Breathnach, R., and Chambon, P. ( 1981) Annu.Rev. Biochem.50,, with the GT-AG rule applied to the splicing point.The cap site maps 44 nucleotides upstream from the translation initiation site.The "TATA box" is located 27 nucleotides upstream from the putative cap site and is flanked by sequences with dyad symmetry.The TATA box can thus be placed in the loop portion of a possible stemloop structure formed by intrastrand base-pairing.Other characteristic nucleotide sequences in the 5' flanking region include a CCAAC pentamer, a 14-base pair (bp) enhancer-like sequence, and a 9-bp sequence homologous to the glucocorticoid responsive element.A long (90 bp) direct repeat and several alternating purinelpyrimidine sequences are also present in the 5' flanking region.A 736-bp sequence of the 5' flanking region adjacent to the cap site of the human AFP gene shows a 61% similarity with the corresponding region of the mouse AFP gene.There are two Alu family sequences and two poly(dT-dG) repeats in the human AFP gene that show different distribution patterns from those in the mouse AFP gene.a-Fetoprotein (AFP') is a major serum protein during fetal life (1-3).Interest in the AFP gene stems from the fact that it is developmentally regulated and often re-expressed at high levels in hepatocarcinoma and teratocarcinoma patients (4, 5).In addition, its similarities to albumin in certain physico-