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J. Biol. Chem., Vol. 277, Issue 12, 9870-9879, March 22, 2002
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From the Pathology Department, Upstate Medical University, State
University of New York, Syracuse, New York 13210
Transforming growth factor
Transforming Growth Factor
1 Induces Proliferation
in Colon Carcinoma Cells by Ras-dependent,
smad-independent Down-regulation of p21cip1*
1 (TGF1) can act
as a tumor suppressor or a tumor promoter depending on the
characteristics of the malignant cell. We recently demonstrated that
colon carcinoma cells transfected with oncogenic cellular
K-rasV12, but not oncogenic cellular H-rasV12,
switched from TGF1-insensitive to TGF1-growth-stimulated and also
became more invasive (Yan, Z., Deng, X., and Friedman, E. (2001)
J. Biol. Chem. 276, 1555-1563). We now demonstrate
that TGF1 growth stimulation of colon carcinoma cells is
Ras-dependent and smad-independent. In U9 colon carcinoma
cells, which are responsive to TGF1 by growth stimulation, a
truncating mutation at Gln-311 was found in the
smad4 gene. Very little smad4 protein was detected in these cells. Loss of smad4 protein was confirmed by functional studies. In U9 cells co-transfected wild-type smad4, but
not mutant smad4, mediated response of the 3TP-lux and pSBE
promoter reporter constructs to TGF1. Proliferation initiated by
TGF1 in U9 cells required Ras-mediated down-regulation of p21cip1
protein. Less p21cip1 was associated with cdk2·cyclin
complexes in TGF1-treated U9 cells, and the cdk2 complexes
had increased kinase activity. Elevation of p21cip1 levels diminished
proliferative response to TGF1. U9 cells expressing DN-N17ras
neither proliferated in response to TGF1 nor down-regulated the cdk
inhibitor p21cip1, and TGF1 activation of 3TP-lux in U9 cells was
inhibited by DN-N17ras in a dose-dependent manner. TGF1
also decreased p21cip1 levels and stimulated proliferation in SW480
cells, which express mutant K-Ras but no smad4 protein. TGF1 did not
activate or inhibit the p21cip1 promoter construct in U9 cells even in
the presence of co-transfected smad4, or alter p21cip1 mRNA levels.
Thus the decrease in p21cip1 levels was mediated by a TGF-initiated
Ras-dependent, but smad-independent post-transcriptional mechanism.
*
This work was supported by Public Health Service Award RO1
CA75708 (to E. F.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pathology,
Upstate Medical University, 2303 Weiskotten Hall, 750 East Adams St.,
Syracuse, NY 13210. Tel.: 315-464-7138; Fax: 315-464-8419; E-mail:
friedmae@mail.upstate.edu.
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