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Volume 271, Number 37, Issue of September 13, 1996 pp. 22368-22375
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Altered Transforming Growth Factor  Signaling in Epithelial Cells when Ras Activation Is Blocked

(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 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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