In:
Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3877-3877
Abstract:
Adult T-cell leukemia (ATL) is a mature CD4+ T-cell malignancy caused by infection with human T-lymphotrophic virus (HTLV-1) and is associated with a marked hypercalcemia on many patients. Recently, it is proposed that Macrophage inflammatory protein-1α (MIP-1α) is the clinical hallmark of hypercalcemia in ATL, but the regulation of MIP-1α secretion has not been clarified yet. In this study, we examined the effect of calcium on the MIP-1α secretion and cell proliferation of ATL cells, and also the role of the Ca2+/calmodulin (CaM)-dependent protein kinase (CaM-K) cascade in transcriptional activation of MIP-1α. The addition of calcium nitrate to the medium enhanced the secretion of MIP-1α by ATL cell lines (ATN, MT-2, OKM-2T) and the proliferation in a dose dependent manner. The maximum response of MIP-1α secretion was induced at 10.42mM calcium in OKM-2T cells. CaM-KK selective inhibitor STO-609 inhibited the calcium dependent secretion of MIP-1α and proliferation of ATL cell lines. We investigated the effects of CaM-KK/CaM-KIV signaling pathway on MIP-1α promoter activity in OKM-2T. The transfection of CaM-KIV stimulated the MIP-1α promoter activity and the upstream kinase, CaM-KK enhanced the stimulatory effect of CaM-KIV on its activity. Furthermore, mutation of the cAMP response element (CRE) within the MIP-1α promoter significantly reduced the effect of CaM-KIV and calcium, and it wasn’t less enhanced by the addition of calcium nitrate to the medium than the wild type. Our studies have indicated that hypercalcemia enhances MIP-1α secretion and the cell growth in ATL cells, and these mechanisms require the CaM-KK/CaM-KIV cascade. These findings raise the possibility that the inhibitory of CaM-KK/CaM-KIV cascade may be of therapeutic value for ATL.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V108.11.3877.3877
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2006
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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