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Papers In Press, published online ahead of print January 9, 2002
Department of Pathology, Upstate Medical University, Syracuse, NY 13210
Corresponding Author: friedmae{at}mail.upstate.edu
TGFß1 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 TGFß1-insensitive to TGFß1-growth stimulated and also became more invasive (J Biol Chem 276:1555, 2001). We now demonstrate that TGFß1 growth stimulation of colon carcinoma cells is ras-dependent and smad-independent. In U9 colon carcinoma cells, which are responsive to TGFß1 by growth stimulation, a truncating mutation at Q311 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 TGFß1. Proliferation initiated by TGFß1 in U9 cells required ras-mediated downregulation of p21cip1 protein. Less p21cip1 was associated with cdk2/cyclin complexes in TGFß1-treated U9 cells, and the cdk2 complexes had increased kinase activity. Elevation of p21cip1 levels diminished proliferative response to TGFß1. U9 cells expressing DN-N17ras neither proliferated in response to TGFß1 nor downregulated the cdk inhibitor p21cip1, and TGFß1 activation of 3TP-lux in U9 cells was inhibited by DN-N17ras in a dose-dependent manner. TGFß1 also decreased p21cip1 levels and stimulated proliferation in SW480 cells which express mutant K-ras but no smad4 protein. TGFß1 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 TGFß initiated ras-dependent, but smad-independent post-transcriptional mechanism.
J. Biol. Chem, 10.1074/jbc.M107646200
Submitted on August 9, 2001
Revised on November 6, 2001
Accepted on January 8, 2002
TGFß1 induces proliferation in colon carcinoma cells by Ras-dependent, Smad-independent downregulation of p21cip1
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