The role of calcium/calmodulin-dependent protein kinase cascade on MIP-1α gene expression of ATL cells

Kensuke Matsumoto, Koji Murao, Hitomi Imachi, Takamasa Nishiuchi, Wenming Cao, Xiao Yu, Junhua Li, Rania A.M. Ahmed, Hisakazu Iwama, Ryoji Kobayashi, Hiroshi Tokumitsu, Toshihiko Ishida

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Abstract

Objective: Adult T-cell leukemia (ATL) is a mature CD4+ T-cell malignancy caused by infection with human T-lymphotrophic virus type-1 and is associated with a marked hypercalcemia in many patients. Recently, it has been proposed that macrophage inflammatory protein-1α (MIP-1α) is the clinical hallmark of hypercalcemia in ATL. In this study, we investigated the effect of extracellular calcium on MIP-1α secretion in ATL cells and the role of Ca2+/calmodulin (CaM)-dependent protein kinase (CaM-K) cascade in transcriptional activation of MIP-1α. Materials and Methods: MIP-1α protein levels in the culture supernatant collected from ATL cells were measured by enzyme-linked immunosorbent assay. Reporter plasmid containing the MIP-1α promoter was transfected to ATL cells, and the promoter activity was measured by luciferase assay. Results: The addition of calcium to the culture medium enhanced the secretion of MIP-1α from ATL cells, which was inhibited by the CaM-KK inhibitor. The transfection of CaM-KIV stimulated MIP-1α promoter activity, and the upstream kinase CaM-KK enhanced the stimulatory effect of CaM-KIV on the promoter activity. Mutation in the cyclic adenosine 5′ monophosphate response element (CRE) within the MIP-1α promoter significantly reduced the effect of CaM-KIV, and CRE mutant promoter activity was not significantly enhanced by the addition of calcium to the culture medium as compared to wild-type promoter activity. Conclusion: Hypercalcemia enhances MIP-1α secretion in ATL cells, and this mechanism requires the involvement of CaM-KK/CaM-KIV cascade through the CRE. These findings raise a possibility that the inhibitory effect of CaM-KK/CaM-KIV cascade may be a potential therapeutic target for ATL.

Original languageEnglish
Pages (from-to)390-400
Number of pages11
JournalExperimental Hematology
Volume36
Issue number4
DOIs
Publication statusPublished - Apr 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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  • Cite this

    Matsumoto, K., Murao, K., Imachi, H., Nishiuchi, T., Cao, W., Yu, X., Li, J., Ahmed, R. A. M., Iwama, H., Kobayashi, R., Tokumitsu, H., & Ishida, T. (2008). The role of calcium/calmodulin-dependent protein kinase cascade on MIP-1α gene expression of ATL cells. Experimental Hematology, 36(4), 390-400. https://doi.org/10.1016/j.exphem.2007.11.013