The human CYP19 (aromatase P450) gene:: update on physiologic roles and genomic organization of promoters
The human CYP19 (aromatase P450) gene:: update on physiologic roles and genomic organization of promoters
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DOI：
10.1016/s0960-0760(03)00359-5
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发表时间：
2003-09-01
影响因子：
4.1
通讯作者：
Shozu, M
中科院分区：
文献类型：
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作者：
Bulun, SE;Sebastian, S;Shozu, M
人类CYP19 （P450arom）基因位于染色体15q21.2区，由一个30 kb的编码区和一个93 kb的调控区组成。基于互联网的人类基因组计划数据使我们能够阐明其复杂的组织结构。异常大的调控区域包含10个组织特异性启动子，可在各种细胞类型中交替使用。每个启动子都受DNA和转录因子中一组不同的调控序列和与这些特定序列结合的转录因子的调控。在大多数哺乳动物中，P450arom的表达受性腺和脑特异性启动子的控制。然而，在人类中，至少有8个额外的启动子似乎是通过DNA的改变在整个进化过程中被招募的。允许招募如此大量启动子的关键机制之一似乎是共同剪接受体位点的极度混杂性，因为每个启动子的激活会导致未翻译的第一外显子剪接到编码区翻译起始位点上游的共同连接点上。这些部分组织特异性启动子用于性腺、骨、脑、血管组织、脂肪组织、皮肤、胎儿肝脏和胎盘的生理性雌激素生物合成。通过分析乳腺癌组织中P450arom mRNA，克隆出了最新表征的启动子（1.7）。这种无tata的启动子在乳腺癌组织中转录了29-54%的P450arom mrna，并含有与内皮型转录因子（如GATA-2）相互作用的内皮型顺式作用元件。我们假设这个启动子可能上调血管内皮细胞中芳香化酶的表达。然而，启动子1.7在健康组织中的体内细胞分布和生理作用尚不清楚。性腺使用位于近端的启动子II。另一方面，正常乳腺脂肪组织主要通过位于共同编码区上游73 kb的启动子1.4维持低水平的芳香酶表达。启动子1.3和启动子II仅在正常乳腺脂肪组织中少量使用。然而，启动子II和1.3在乳腺癌中的活性显著增加。此外，内皮型启动子1.7在乳腺癌中也上调。因此，原型雌激素依赖性恶性乳腺癌似乎利用四种启动子（II, 1.3,1.7和1.4）来表达芳香化酶。与正常乳腺相比，这四种启动子产生的P450arom mRNA种类的总和显著增加了乳腺癌中P450arom mRNA的总水平。(C) 2003, Elsevier Ltd.出版
The human CYP19 (P450arom) gene is located in the chromosome 15q21.2 region and is comprised of a 30 kb coding region and a 93 kb regulatory region. The Internet-based Human Genome Project data enabled us to elucidate its complex organization. The unusually large regulatory region contains 10 tissue-specific promoters that are alternatively used in various cell types. Each promoter is regulated by a distinct set of regulatory sequences in DNA and transcription factors that bind to these specific sequences. In most mammals, P450arom expression is under the control of gonad- and brain-specific promoters. In the human, however, there are at least eight additional promoters that seemed to have been recruited throughout the evolution possibly via alterations in DNA. One of the key mechanisms that permit the recruitment of such a large number of promoters seems to be the extremely promiscuous nature of the common splice acceptor site, since activation of each promoter gives rise splicing of an untranslated first exon 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 physiologic estrogen biosynthesis.The most recently characterized promoter (1.7) was cloned by analyzing P450arom mRNA in breast cancer tissue. This TATA-less promoter accounts for the transcription of 29-54% of P450arom mRNAs in breast cancer tissues and contains endothelial-type cis-acting elements that interact with endothelial-type transcription factors, e.g. GATA-2. We hypothesize that this promoter may upregulate aromatase expression in vascular endothelial cells. The in vivo cellular distribution and physiologic roles of promoter 1.7 in healthy tissues, however, are not known.The gonads use the proximally located promoter II. The normal breast adipose tissue, on the other hand, maintains low levels of aromatase expression primarily via promoter 1.4 that lies 73 kb upstream of the common coding region. Promoters 1.3 and II are used only minimally in normal breast adipose tissue. Promoters II and 1.3 activities in the breast cancer, however, are strikingly increased. Additionally, the endothelial-type promoter 1.7 is also upregulated in breast cancer. Thus, it appears that the prototype estrogen-dependent malignancy breast cancer takes advantage of four promoters (II, 1.3,1.7 and 1.4) for aromatase expression. The sum of P450arom mRNA species arising from these four promoters markedly increase total P450arom mRNA levels in breast cancer compared with the normal breast. (C) 2003 Published by Elsevier Ltd.