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G Colon-Otero, JJ Sando, JL Sims, E McGrath, DE Jensen and PJ Quesenberry
The effects of adenosine diphosphate (ADP) ribosylation inhibitors on
hematopoietic growth factor-induced proliferation were examined.
Significant inhibition of interleukin-3 (IL-3), colony-stimulating factor
1, and lung conditioned media-induced clonal agar growth of normal murine
hematopoietic cells by 10 mmol/L nicotinamide (NAM), 10 mmol/L
3-aminobenzamide (3AB), and 5 mmol/L N1-methylnicotinamide (1MN) was noted.
Nicotinic acid, a related compound that does not inhibit ADP ribosylation,
failed to inhibit the growth factor-mediated proliferation. NAM (10
mmol/L), 3AB (10 mmol/L), and 1MN (5 mmol/L) also prevented IL-3 and
phorbol ester-stimulated 3H-thymidine incorporation into the
IL-3-responsive FDC-P1 cell line. Exposure of FDC-P1 cells to 10 mmol/L NAM
led to a significant decrease in nuclear poly-(ADP-ribose) levels. Exposure
of FDC-P1 cells to 5 mmol/L 1MN did not affect the interaction of the
phorbol ester receptor, protein kinase-C (PK-C), with the cell membrane as
determined by assay of phorbol ester binding in cytosol and membrane
preparations. Nor did it affect the catalytic activity of PK-C as
determined by assaying the in vitro phosphorylation of histone H1 by
cytosolic kinase preparations from FDC-P1 as well as EL4 thymoma cells. 1MN
markedly enhanced the inhibitory effects of phorbol esters on DNA synthesis
of EL4 cells even at concentrations (1.25 mmol/L) that had no effects on
DNA synthesis in the absence of phorbol esters. Our findings demonstrate
that (a) active ADP ribosylation inhibitors interfere with growth
factor-induced proliferation of murine hematopoietic cells and (b) the
inhibition occurs at a step that follows the activation and translocation
of PK-C and is more closely linked to DNA synthesis.
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| Copyright © 1987 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||