Document Detail

Multiple doses of diacylglycerol and calcium ionophore are necessary to activate AP-1 enhancer activity and induce markers of macrophage differentiation.
MedLine Citation:
PMID:  2120223     Owner:  NLM     Status:  MEDLINE    
In contrast to phorbol esters, multiple doses of diacylgycerols are needed to differentiate U937 human monoblastic leukemic cells to a macrophage-like phenotype. Although both of these agents similarly activate protein kinase C in vitro, it is not known why these agents appear to have differing biologic effects. One possibility is that they regulate gene transcription in slightly different ways. Regulation of gene transcription by phorbol esters is complex and involves the stimulation of the transactivating proteins Jun and Fos which form dimers and bind to the AP-1 enhancer elements (5'-TGAGTCA-3'). To understand whether diacylglycerols regulate gene transcription similarly to phorbol esters and to examine whether activation of AP-1 enhancer activity is correlated with differentiation, we have treated U937 human monoblastic leukemic cells with these agents and examined activation of transcription from AP-1 enhancer elements. We find that, although a single dose of diacylglycerol, like phorbol esters, is sufficient to elevate mRNA levels of both the c-jun and c-fos protooncogenes, in contrast to phorbol esters there is no increase in either Jun protein or activation of AP-1 enhancer activity. However, multiple doses of this agent given over 24 h stimulate repeated elevations in c-jun and c-fos mRNA, increases in Jun protein, and enhancer activation. Treatment of U937 cells with ionomycin, a calcium ionophore, also stimulates an increase in c-jun mRNA, but neither activates AP-1 enhancer activity nor stimulates differentiation of these cells. However ionomycin functions to enhance the effects of diacylglycerols both on transcriptional activation and U937 differentiation. These results suggest a complex regulation of AP-1 enhancer activity in U937 cells by diacylglycerols involving both transcriptional and post-transcriptional regulatory mechanisms. Maximal activation of AP-1 enhancer elements, and not changes in jun and fos mRNA, is correlated with increases in markers of U937 differentiation. These changes may be important in the early events leading to differentiation of hematopoietic cells.
F William; F Wagner; M Karin; A S Kraft
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  265     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1990 Oct 
Date Detail:
Created Date:  1990-11-15     Completed Date:  1990-11-15     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  18166-71     Citation Subset:  IM    
Division of Hematology/Oncology, University of Alabama, Birmingham 35294.
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MeSH Terms
Blotting, Northern
Cell Differentiation
DNA-Binding Proteins / genetics,  physiology
Diglycerides / administration & dosage*
Drug Administration Schedule
Enhancer Elements, Genetic*
Ionomycin / administration & dosage*
Macrophages / cytology*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins c-fos
Proto-Oncogene Proteins c-jun
RNA, Messenger / genetics
Tetradecanoylphorbol Acetate / pharmacology
Time Factors
Transcription Factors / genetics,  physiology
Tumor Cells, Cultured
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Diglycerides; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/Transcription Factors; 1069-87-0/1,2-dioctanoylglycerol; 16561-29-8/Tetradecanoylphorbol Acetate; 56092-81-0/Ionomycin

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