Activation of the transcription factor kappa B in human KG-1 myeloid leukemia cells treated with 1-beta-D-arabinofuranosylcytosine

MA Brach, SM Kharbanda, F Herrmann and DW Kufe

Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.

The present studies have examined the effects of 1-beta-D- arabinofuranosylcytosine (ara-C) on activation of the transcription factor kappa B (NF-kappa B). The results demonstrate that treatment of human KG-1 myeloid leukemia cells with ara-C is associated with induction of protein binding to the NF-kappa B consensus sequence. NF- kappa B binding was activated at 30 min and reached maximal levels of binding at 1-2 hr of ara-C treatment. The NF-kappa B consensus sequence was ligated to the heterologous thymidine kinase (TK) promoter and the human growth hormone (GH) reporter gene to determine whether ara-C- induced NF-kappa B activity includes an enhancer function. Ara-C treatment had little effect on transient expression of pTKGH in KG-1 cells but increased transcription of the p (NF-kappa B) TKGH vector by 8-fold. The results also demonstrate that ara-C transiently increases NF-kappa B mRNA levels. However, the finding that ara-C-induced binding of NF-kappa B to DNA occurs in the presence of cycloheximide indicates that this agent activates preexisting NF-kappa B protein. These results suggest that ara-C induces a cytoplasmic pathway that transduces signals to the nucleus by activation of NF-kappa B.

Volume 41, Issue 1, pp. 60-63, 01/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics