Organization of the human aromatase p450 (CYP19) gene.
The human CYP19 (p450arom) gene is located in the 21.2 region on the long arm of chromosome 15 (15q21.2). This gene spans a region that consists of a 30 kb coding region and a 93 kb regulatory region ( approximately 123 kb total length). Its regulatory region contains at least 10 distinct promoters regulated in a tissue- or signaling pathway-specific manner. The Human Genome Project data published in 2000 enabled us to accurately align these promoters within the 93 kb regulatory region of the p450arom gene. Each promoter is regulated by a distinct set of regulatory sequences in DNA and transcription factors that bind to these specific sequences. In most vertebrates, p450arom expression is under the control of gonad- and brain-specific promoters. In humans, however, there are at least eight additional promoters that were apparently recruited throughout evolution, possibly via alterations in DNA. A critical mechanism that permits the use of such a large number of promoters seems to be the extremely promiscuous nature of the common splice acceptor site because, with activation of each promoter, an untranslated first exon is spliced onto this common junction immediately upstream of the translation start site in the coding region. These partially tissue-specific promoters are used in the gonads, bone, brain, vascular tissue, adipose tissue, skin, fetal liver, and placenta for estrogen biosynthesis necessary for human physiology. Ovary and testis use promoter II, which is located immediately upstream of the coding region. The adipose tissue in general, including adipose tissue of the disease-free breast, on the other hand, maintains low levels of aromatase expression primarily via promoter I.4, which lies 73 kb upstream of the common coding region. Promoters I.3 and II are used only minimally in normal breast adipose tissue. Promoter II and I.3 activities in breast cancer tissue, however, are strikingly increased. Additionally, the endothelial-type promoter I.7 is also upregulated in breast cancer. Therefore, breast tumor tissue takes advantage of four promoters (II, I.3, I.7, and I.4) for aromatase expression and estrogen production. The sum of p450arom mRNA species arising from these four promoters contributes significantly to elevated levels of total p450arom mRNA in breast cancer in contrast to the normal breast that uses promoter I.4. Because each mRNA species contains the identical coding region regardless of the variable untranslated first exon, the encoded protein functions as the aromatase enzyme in each case.
Bulun, SE; Takayama, K; Suzuki, T; Sasano, H; Yilmaz, B; Sebastian, S
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