Transforming growth factor beta(1) is an important growth regulator in many
cell types, usually exerting a negative effect on cellular growth. Inhibit
ion of DNA synthesis and cell proliferation is frequently lost during malig
nant transformation, and in some cases, tumor cell proliferation is actuall
y stimulated by TGF-beta(1). The present study demonstrates a novel link be
tween alterations in TGF-beta(1), regulation during malignant conversion, a
nd the expression of ferritin, an important activity involved in a number o
f biological functions including iron homeostasis and cell-growth control.
A series of H-ras-transformed mouse 10 T 1/2 cell lines, exhibiting increas
ing malignant potential, was investigated for possible TGF-beta(1)-mediated
changes in ferritin gene expression. Selective induction of gene expressio
n was observed, since only H-ras-transformed cells with malignant potential
exhibited marked elevations in ferritin gene expression, in particular, al
terations in H-ferritin gene expression. The regulation of H-ferritin gene
expression in response to TGF-beta(1) did not involve alterations in transc
ription, but occurred through mechanisms of post-transcriptional stabilizat
ion of the H-ferritin mRNA. Additionally, evidence was obtained for a cyclo
heximide-sensitive regulator of H-ferritin gene expression, since the prese
nce of this protein synthesis inhibitor increased
H-ferritin message levels, and in combination with TGF-beta(1), cooperated
in an additive manner to augment H-ferritin gene expression. These results
show for the first time that TGF-beta(1) can regulate ferritin gene express
ion in malignant H-ras transformed cells, and suggest a mechanism for growt
h factor stimulation of malignant cells, in which early alterations in the
control of H-ferritin gene expression are important.