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

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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
Issue number4
Publication statusPublished - Apr 2008
Externally publishedYes

ASJC Scopus subject areas

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


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