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

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-1alpha (MIP-1alpha) is the clinical hallmark of hypercalcemia in ATL. In this study, we investigated the effect of extracellular calcium on MIP-1alpha secretion in ATL cells and the role of Ca(2+)/calmodulin (CaM)-dependent protein kinase (CaM-K) cascade in transcriptional activation of MIP-1alpha.

MATERIALS AND METHODS:

MIP-1alpha protein levels in the culture supernatant collected from ATL cells were measured by enzyme-linked immunosorbent assay. Reporter plasmid containing the MIP-1alpha 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-1alpha from ATL cells, which was inhibited by the CaM-KK inhibitor. The transfection of CaM-KIV stimulated MIP-1alpha 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-1alpha 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-1alpha 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.

• Authors: 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
• Journal: Experimental hematology (Exp Hematol) Vol. 36 Issue 4 Pg. 390-400 (Apr 2008) ISSN: 0301-472X [Print] Netherlands
• PMID: 18249060 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• Chemokine CCL3
• Enzyme Inhibitors
• Isoquinolines
• Naphthalimides
• STO 609
• Calcium-Calmodulin-Dependent Protein Kinase Kinase
• Calcium-Calmodulin-Dependent Protein Kinases
• Calcium

Topics

• Benzimidazoles (pharmacology)
• Calcium (pharmacology)
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (antagonists & inhibitors)
• Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
• Cell Line, Tumor
• Chemokine CCL3 (genetics, metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Isoquinolines (pharmacology)
• Leukemia, T-Cell (drug therapy, metabolism)
• Naphthalimides (pharmacology)
• Phosphorylation (drug effects)
• Promoter Regions, Genetic
• Signal Transduction (drug effects)