論文 - 詳細
RRC ID | 43260 |
---|---|
著者 | Matsumoto K, Murao K, Imachi H, Nishiuchi T, Cao W, Yu X, Li J, Ahmed RA, Iwama H, Kobayashi R, Tokumitsu H, Ishida T. |
タイトル | The role of calcium/calmodulin-dependent protein kinase cascade on MIP-1alpha gene expression of ATL cells. |
ジャーナル | Exp Hematol |
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. |
巻・号 | 36(4) |
ページ | 390-400 |
公開日 | 2008-4-1 |
DOI | 10.1016/j.exphem.2007.11.013 |
PII | S0301-472X(07)00688-1 |
PMID | 18249060 |
MeSH | Benzimidazoles / pharmacology Calcium / pharmacology Calcium-Calmodulin-Dependent Protein Kinase Kinase / antagonists & inhibitors Calcium-Calmodulin-Dependent Protein Kinases / metabolism* Cell Line, Tumor Chemokine CCL3 / genetics Chemokine CCL3 / metabolism* Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Gene Expression Regulation, Leukemic / drug effects* Humans Isoquinolines / pharmacology Leukemia, T-Cell / drug therapy Leukemia, T-Cell / metabolism* Naphthalimides / pharmacology Phosphorylation / drug effects Promoter Regions, Genetic Signal Transduction / drug effects* |
IF | 2.82 |
引用数 | 7 |
WOS 分野 | MEDICINE, RESEARCH & EXPERIMENTAL HEMATOLOGY |
リソース情報 | |
ヒト・動物細胞 | ATN-1(RCB1440) Jurkat(RCB0806) |