Analysis of transcriptional regulation of human breast aromatase by in vitro and in vivo studies.
Aromatase mRNA in normal breast tissues is mainly transcribed from exon 1b (I.4) of the gene. However, in breast cancer tissues, it is often transcribed from exon 1c/1d (I.3/PII). Such a switching from exon 1b to exon 1c/1d has often found concomitantly with elevated levels of aromatase mRNA. To elucidate the molecular mechanism of a switching of multiple exons 1 and enhanced expression of aromatase in the breast tissues, we identified essential elements responsible for transcription from exon 1b. Gel shift assays indicated that there are two essential elements for transcription from exon 1b between -300 and -500 bp in the promoter region. The two unique elements have homologous consensus DNA sequences, and competed for binding of the specific nuclear protein with each other. We next generated transgenic mouse expressing a reporter gene controlled by multiple promoters in the human aromatase gene. The mouse gave tissue-specific expression of the reporter gene and tissue-specific utilization of the alternative promoter regions. These results show that this transgenic mouse is a good model animal for the study of tissue-specific regulation of human aromatase gene.
Harada
N
N
Department of Biochemistry, School of Medicine, Fujita Health University, Toyoake, 470-1192, Aichi, Japan. nharada@fujita-hu.ac.jp
Matsumoto
T
T
Yoshimura
N
N
Sakamoto
H
H
Honda
S
S
D017398:Alternative Splicing; D000818:Animals; D001141:Aromatase / Q000235:genetics*; D001483:Base Sequence; D001940:Breast / Q000201:enzymology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics; D002478:Cells, Cultured; D016384:Consensus Sequence; D004247:DNA / Q000235:genetics; D005091:Exons; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D066298:In Vitro Techniques; D007763:Lac Operon; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D012333:RNA, Messenger; D004247:DNA; D001141:Aromatase