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Activation of the AP-1 transcription factor by arabinofuranosylcytosine in
myeloid leukemia cells
MA Brach, F Herrmann and DW Kufe
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Boston,
MA 02115.
Previous studies have shown that 1-beta-D-arabinofuranosylcytosine (ara- C)
induces transcription of the c-jun immediate early response gene in human
myeloid leukemia cells. The present work has examined the mechanisms
responsible for this effect. Deleted forms of the c-jun promoter were
linked to the chloramphenicol acetyltransferase (CAT) gene and transfected
into KG-1 cells. The results demonstrate that ara- C-induced c-jun
transcription is mediated by an element between positions -74 and -20
upstream to the start site. Electrophoretic mobility shift assays with the
fragment f(-74/-20) showed an increase in binding with nuclear proteins
from ara-C-treated cells as compared with untreated cells. Competition with
an oligonucleotide containing the AP-1 consensus sequence indicated that
ara-C stimulates binding of nuclear proteins at the AP-1 site in the c-jun
promoter. These findings were confirmed in other gel shift studies with the
collagenase enhancer AP-1 consensus sequence and with a DNA fragment
containing an altered AP-1 site. The binding of JUN/AP-1 was maximal at 1
hour of ara-C treatment and decreased to baseline levels at 12 hours. The
finding that ara-C induces AP-1 binding in the absence of protein synthesis
indicated that this agent activates already synthesized JUN/AP-1. To
confirm these findings, the AP-1 consensus sequence was introduced 5' to
the heterologous SV40 promoter. The results show that AP-1 enhances SV40
promoter activity in ara-C-treated cells. Taken together, these findings
indicate that: (1) enhancement of JUN/AP-1 activity in ara-C- treated cells
involves a posttranslational modification of JUN/AP-1; and (2) binding of
activated JUN/AP-1 to the AP-1 site in the c-jun promoter confers ara-C
inducibility of this gene.
Volume 79,
Issue 3,
pp. 728-734,
02/01/1992
Copyright © 1992 by The American Society of Hematology
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