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
Externally publishedYes

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Macrophage Inflammatory Proteins
Adult T Cell Leukemia Lymphoma
Calcium-Calmodulin-Dependent Protein Kinases
Calmodulin
Gene Expression
Hypercalcemia
Calcium
Culture Media
Response Elements
Luciferases
Cyclic AMP
Transcriptional Activation
Transfection
Plasmids
Phosphotransferases
Enzyme-Linked Immunosorbent Assay
Viruses
T-Lymphocytes
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

The role of calcium/calmodulin-dependent protein kinase cascade on MIP-1α gene expression of ATL cells. / Matsumoto, Kensuke; Murao, Koji; Imachi, Hitomi; Nishiuchi, Takamasa; Cao, Wenming; Yu, Xiao; Li, Junhua; Ahmed, Rania A M; Iwama, Hisakazu; Kobayashi, Ryoji; Tokumitsu, Hiroshi; Ishida, Toshihiko.

In: Experimental Hematology, Vol. 36, No. 4, 04.2008, p. 390-400.

Research output: Contribution to journalArticle

Matsumoto, K, Murao, K, Imachi, H, Nishiuchi, T, Cao, W, Yu, X, Li, J, Ahmed, RAM, 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, vol. 36, no. 4, pp. 390-400. https://doi.org/10.1016/j.exphem.2007.11.013
Matsumoto, Kensuke ; Murao, Koji ; Imachi, Hitomi ; Nishiuchi, Takamasa ; Cao, Wenming ; Yu, Xiao ; Li, Junhua ; Ahmed, Rania A M ; Iwama, Hisakazu ; Kobayashi, Ryoji ; Tokumitsu, Hiroshi ; Ishida, Toshihiko. / The role of calcium/calmodulin-dependent protein kinase cascade on MIP-1α gene expression of ATL cells. In: Experimental Hematology. 2008 ; Vol. 36, No. 4. pp. 390-400.
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AU - Cao, Wenming

AU - Yu, Xiao

AU - Li, Junhua

AU - Ahmed, Rania A M

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AU - Tokumitsu, Hiroshi

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