Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin

Hiromi Ito, Masashi Murakami, Ayako Furuhata, Siqiang Gao, Kayo Yoshida, Sayaka Sobue, Kazumi Hagiwara, Akira Takagi, Tetsuhito Kojima, Motoshi Suzuki, Yoshiko Banno, Kouji Tanaka, Keiko Tamiya-Koizumi, Mamoru Kyogashima, Yoshinori Nozawa, Takashi Murate

研究成果: Article

35 引用 (Scopus)

抜粋

Mg 2+-dependent neutral SMases (NSMases) have emerged as prime candidates for stress-induced ceramide production. Among isoforms identified, previous reports have suggested the importance of NSMase2. However, its activation mechanism has not been precisely reported. Here, we analyzed the mechanism of NSMase2 gene expression by the anti-cancer drug, daunorubicin (DA). DA increased cellular ceramides (C16, C18 and C24) and NSMase activity of a human breast cancer cell line, MCF-7. DA remarkably increased the NSMase2 message and protein, whereas little change in NSMase1 and NSMase3 mRNAs and only a mild increase in acid SMase mRNA were observed. Overexpression and a knock down of NSMase2 indicated that NSMase2 played a role in DA-induced cell death. NSMase2 promoter analysis revealed that three Sp1 motifs located between -148 and -42bp upstream of the first exon were important in basic as well as in DA-induced promoter activity. Consistently, luciferase vectors containing three consensus Sp1-motifs but not its mutated form showed DA-induced transcriptional activation. DA-treated MCF-7 showed increased Sp3 protein. In SL2 cells lacking Sp family proteins, both Sp1 and Sp3 overexpression increased NSMase promoter activity. Increased binding of Sp family proteins by DA to three Sp1 motifs was shown by electrophoresis mobility shift and ChIP assays.

元の言語English
ページ(範囲)681-690
ページ数10
ジャーナルBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
1789
発行部数11-12
DOI
出版物ステータスPublished - 11-2009

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Ito, H., Murakami, M., Furuhata, A., Gao, S., Yoshida, K., Sobue, S., Hagiwara, K., Takagi, A., Kojima, T., Suzuki, M., Banno, Y., Tanaka, K., Tamiya-Koizumi, K., Kyogashima, M., Nozawa, Y., & Murate, T. (2009). Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1789(11-12), 681-690. https://doi.org/10.1016/j.bbagrm.2009.08.006