Dissociation of nuclear events on p21 RAS transformation of FDC-P1 myeloid
cells: c-jun/AP-1 expression versus c-myc transcription
S Litz-Jackson, AH Miller, GS Burgess and HS Boswell
Division of Hematology/Oncology, Indiana University School of Medicine,
Indianapolis.
We have previously reported transformation to growth factor-independent
proliferation in the interleukin-3 (IL-3)-dependent cell line FDC-P1 by
high-level expression of the valine 12 Harvey RAS oncogene, following from
a nonautocrine mechanism. The present study was undertaken to examine
nuclear tertiary messenger, transcriptional response gene expression to
deduce the intracellular signaling pathways responsible for this autonomous
proliferation. We confirmed other reports that transformed
p21RAS-expressing cells constitutively express the transcription factor
complex jun/AP-1, in this case resulting from the ongoing expression of the
c-jun and c-fos genes in the absence of IL-3. However, the ongoing growth
factor independent expression of c-myc by a transcriptional mechanism in
FDC-P1 cells expressing p21 RAS cannot be explained by intracellular
signaling in the jun/AP-1 (protein kinase C) pathway. This conclusion
derives from the observation that c-jun expression mediated via protein
kinase C activation with phorbol ester (12-0-tetra
decanoylphorbol-13-acetate, TPA) treatment does not lead to c-myc
expression in parent FDC-P1 cells. On the contrary, FDC-P1 cells stably
transfected with a c-myc gene controlled under the influence of a
metallothionein IIA promoter (containing the TPA-responsive element [TRE])
express the transfected MTIIA-c-myc and downregulate the endogenous c-myc
in response to protein kinase C activation with TPA. Further, nuclear
proteins derived from cells expressing p21 RAS, which bind specifically to
the purified c-myc P2 promoter, are not competed in their binding to the
motif-rich P2 element by AP-1 oligonucleotide. Therefore, expression of the
Harvey RAS oncogene in FDC-P1 myeloid cells leads to at least two pathways
of cytoplasmic signaling. One pathway involves protein kinase C and
c-jun/AP-1, but another pathway that is protein kinase C-independent
appears to mediate c-myc transcription.
Volume 79,
Issue 9,
pp. 2404-2414,
05/01/1992
Copyright © 1992 by The American Society of Hematology
