International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A27. Characterization of the Promoter of the Murine mac25 Gene

Mitsuo Kato1, Noriyuki Kanemitsu1,2, Tsuneharu Miki2, Sei Komatsu3,4, Yasushi Okazaki3,4, Yoshihide Hayashizaki3,4, and Toshiyuki Sakai1
1Department of Preventive Medicine,
2Department of Urology, Kyoto Prefectural University of Medicine,
Laboratory for Genome Exploration Research Group, RIKEN Genome Science Center (GSC) and Genome Science Laboratory; RIKEN Tsukuba Institute,
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology (JST)

We analyzed the promoter of the murine mac25 gene. The sequence of a phage genomic clone (M33) containing about the 13 kb murine genomic region of the mac25 gene was determined. We found an L1 retrotransposon, which is highly homologous to Tf subfamily L1Md-Tf6 at the upstream of the mac25 gene. The direction of this L1 transposon was opposite to that of the mac25 gene. Two CpG islands were observed. One was in the promoter region of L1 transposon and the other was in the approximately 1 kb region that contained exon 1 of the mac25 gene. As hypermethylation and reduced expression of the mac25 gene was reported in murine liver tumors, methylation of this CpG island around the exon 1 may associate with expression of the mac25 gene and tumorigenesis.

In the promoter region of mac25 gene, we found five repeats of CCAAT sequences, four Sp1 sites, a TATA-like sequence and an initiator (INR) sequence. The INR consensus (PyPyAN(A/T)PyPy, Py = pyrimidine) sequence with one base mismatch (TCACTCg) was also found just after the initiation site. A TATA-like sequence (TTTAA) was found at -29 to -25. TATA boxes are located at 25-30 bp upstream of its transcriptional initiation site in the majority of the eukaryotic promoters. The structure of the murine mac25 gene may be very reasonable for the expression.

Analysis using luciferase reporter plasmids that contain several mutant promoters of the mac25 gene, suggests that CCAAT repeats may have a strong enhancer activity and the second and third Sp1 sites may be essential for basal activity of the expression of the mac25 gene.

The control of the expression of the mac25 gene is very important for cancer therapy and prevention, because of the increasing amount of reports about the reduction of the expression of the mac25 gene in various human cancers.

Although it was reported that the mac25 gene is up-regulated by hormonal factors, we could not find any such hormone receptor responsive elements in the promoter region of the mac25 gene. Regulation of the mac25 gene by hormonal factors may be indirect or mediated by other novel mechanisms. The identification of such regulators may be important not only to determine the mechanism of the gene expression, but also to identify a clue for cancer therapy and prevention.

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