Journal
EXPERIMENTAL CELL RESEARCH
Volume 258, Issue 2, Pages 425-437Publisher
ACADEMIC PRESS INC
DOI: 10.1006/excr.2000.4939
Keywords
vitamin D-3; stress-activated pathways; p38 MAP kinase; JNK1/2 MAP kinase; ERK1/2 MAP kinase
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Funding
- NCI NIH HHS [R01 CA 44722] Funding Source: Medline
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Differentiation therapy for neoplastic diseases has potential for supplementing existing treatment modalities but its implementation has been slow. One of the reasons is the lack of full understanding of the complexities of cellular pathways through which signals for differentiation lead to cell maturation. This was: addressed in this study using HL60 cells, a well-established model of differentiation of neoplastic cells. SE 203580 and SE 202190, specific inhibitors of a signaling protein p38 MAP kinase, were found to markedly accelerate monocytic differentiation of HL60 cells induced by low concentrations of 1,25-dihydroxyvitamin D-3 (1,25D(3)). Surprisingly, inhibition of p38 activity resulted in sustained enhancement of p38 phosphorylation and of its in vitro activity in the absence of the inhibitor, indicating up-regulation of the upstream components of the p38 pathway. In addition, SE 203580 or SE 202190 treatment of HL60 cells resulted in a prolonged activation of the JNK and, to a lesser extent, the ERK pathways, The data are consistent with the hypothesis that in HL60 cells an interruption of a negative feedback loop from a p38 target activates a common regulator of multiple MAPK pathways. The possibility also exists that JNK and/or ERK pathways amplify a differentiation signal provided by 1,25D(3). (C) 2000 Academic Press.
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