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(Received for publication, April 23, 1996, and in revised form, June 10, 1996)
From the Department of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033 and
§ Onyx Pharmaceuticals, Richmond, California 94806
We have previously demonstrated that growth
inhibition of untransformed intestinal epithelial cells by transforming
growth factor
Volume 271, Number 37,
Issue of September 13, 1996
pp. 22368-22375
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Signaling in Epithelial
Cells when Ras Activation Is Blocked
1 (TGF) and TGF2 was
associated with a rapid activation of both Ras and extracellular
signal-regulated kinase 1 (Erk1) (Mulder, K. M., and Morris, S. L. (1992) J. Biol. Chem. 267, 5029-5031; Hartsough, M. T., and Mulder, K. M. (1995) J. Biol. Chem. 270, 7117-7124). In order to determine whether Ras was required for TGF
regulation of both Erk1 and downstream components associated with
TGF-mediated growth inhibition, the intestinal epithelial cell (IEC)
line IEC 4-1 was transfected with a vector containing a
dominant-negative mutant of Ras (RasN17) under the control of an
inducible metallothionein promoter. Using two different
RasN17-transfected clones treated with ZnCl2, we
demonstrate here that induction of Ras expression by at least 4-fold
completely abrogated the TGF-mediated activation of Erk1. Moreover,
the RasN17-mediated reversal of the TGF effect on Erk1 was dependent
upon the level of expression of the dominant-negative protein.
ZnCl2 treatment of control cells transfected with the empty
vector did not alter Ras expression or the activation of Erk1 by
TGF. In order to determine whether the activation of Ras by TGF
was required for the growth inhibitory effect of TGF, we examined
TGF2 effects on Cdk2-associated histone H1 kinase
activity, cyclin A protein expression levels, and DNA synthesis in two
intestinal epithelial cell clones transfected with RasN17. In cells
expressing RasN17, we observed a 50% reversal of the inhibition of
Cdk2 activity, a 78% reversal of the down-regulation of cyclin A
protein expression, and a 21% reversal of the inhibition of DNA
synthesis by TGF. Collectively, these results indicate that Ras
activation is obligatory for TGF-mediated activation of Erk1,
whereas it is partially required for the growth inhibitory effect of
TGF.
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