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(Received for publication, April 1, 1996, and in revised form, May 28, 1996)
From the Lombardi Cancer Center, Georgetown University,
Washington, D. C. 20007
Retinoids are potent regulators of growth and
differentiation and have shown promise as chemotherapeutic agents
against selected cancers in particular squamous cell carcinoma (SCC).
Earlier studies from our laboratory showed that a secreted binding
protein for fibroblast growth factors (BP) is expressed at high levels
in SCC cell lines and tissue samples. Here we investigate whether
retinoids affect BP gene expression in SCC. In six different human SCC
cell lines, we found that all-trans-retinoic acid (tRA)
down-regulated BP mRNA by 39-89% within 24 h. From this
group of cell lines, we selected the ME-180 cell line for more detailed
studies of the mechanisms of this regulation. tRA down-regulated BP
mRNA in a time- and dose-dependent manner. The effect
of tRA was reversible, and BP mRNA returned to control levels
within 24 h after removal of tRA. We also measured BP mRNA
half-life and performed nuclear run-on experiments to study if tRA
down-regulates BP by destabilizing the mRNA and/or by decreasing
the rate of transcription. BP mRNA in ME-180 cells is very stable
with a half-life of >16 h, and tRA decreased BP mRNA with a
half-time of 5 h. Actinomycin D and cycloheximide blocked the tRA
effect, suggesting that transcriptional regulation as well as de
novo protein synthesis contribute to this post-transcriptional
regulation of BP mRNA levels. In addition, tRA decreased the rate
of BP gene transcription by 2- to 3-fold within 1 h. We conclude
that retinoids down-regulate BP gene expression by post-transcriptional
as well as by transcriptional mechanisms.
Volume 271, Number 35,
Issue of August 30, 1996
pp. 21303-21308
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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