Bulun Serdar E, Takayama Kazuto, Suzuki Takashi, Sasano Hironobu, Yilmaz Bertan, Sebastian Siby
Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois 60611, USA.
Semin Reprod Med. 2004 Feb;22(1):5-9. doi: 10.1055/s-2004-823022.
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.
人类CYP19（p450arom）基因位于15号染色体长臂的21.2区域（15q21.2）。该基因跨越一个由30 kb编码区和93 kb调控区组成的区域（总长约123 kb）。其调控区包含至少10个以组织或信号通路特异性方式调控的不同启动子。2000年公布的人类基因组计划数据使我们能够在p450arom基因的93 kb调控区内准确比对这些启动子。每个启动子由一组独特的DNA调控序列和与这些特定序列结合的转录因子调控。在大多数脊椎动物中，p450arom的表达受性腺和脑特异性启动子的控制。然而，在人类中，至少还有八个额外的启动子显然是在整个进化过程中通过DNA改变而被招募的。允许使用如此大量启动子的一个关键机制似乎是常见剪接受体位点的极端混杂性质，因为随着每个启动子的激活，一个未翻译的第一外显子会立即剪接到编码区翻译起始位点上游的这个共同连接处。这些部分组织特异性启动子用于性腺、骨骼、脑、血管组织、脂肪组织、皮肤（胎儿肝脏和胎盘），用于人类生理所需的雌激素生物合成。卵巢和睾丸使用位于编码区紧邻上游的启动子II。另一方面，包括无病乳腺的脂肪组织在内的一般脂肪组织，主要通过位于共同编码区上游73 kb处的启动子I.4维持低水平的芳香化酶表达。启动子I.3和II在正常乳腺脂肪组织中的使用极少。然而，启动子II和I.3在乳腺癌组织中的活性显著增加。此外，内皮型启动子I.7在乳腺癌中也上调。因此，乳腺肿瘤组织利用四个启动子（II、I.3、I.7和I.4）进行芳香化酶表达和雌激素产生。与使用启动子I.4的正常乳腺相比，由这四个启动子产生的p450arom mRNA种类总和对乳腺癌中总p450arom mRNA水平的升高有显著贡献。由于每个mRNA种类无论可变的未翻译第一外显子如何都包含相同的编码区，所以每种情况下编码的蛋白质都作为芳香化酶发挥作用。
