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J. Biol. Chem., Vol. 276, Issue 2, 1555-1563, January 12, 2001

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Oncogenic Ki-ras Confers a More Aggressive Colon Cancer Phenotype through Modification of Transforming Growth Factor- Receptor III^*

Zhongfa Yan, Xiaobing Deng, and Eileen Friedman

From the Department of Pathology, Upstate Medical University, State University of New York, Syracuse, New York 13210

Transforming growth factor-1 (TGF-1) can act as a tumor suppressor or a tumor promoter depending on the characteristics of the malignant cell. Each of three Ki-ras^G12V transfectants of HD6-4 colon cancer cells had been shown to be more aggressive in vivo than controls in earlier studies (Yan, Z., Chen, M., Perucho, M., and Friedman, E. (1997) J. Biol. Chem. 272, 30928-30936). We now show that stable expression of oncogenic Ki-ras^G12V converts the HD6-4 colon cancer cell line from insensitive to TGF-1 to growth-promoted by TGF-1. Each of three Ki-ras^G12V transfectants responded to TGF-1 by an increase in proliferation and by decreasing the abundance of the Cdk inhibitor p21 and the tumor suppressor PTEN, whereas each of three wild-type Ki-ras transfectants remained unresponsive to TGF-1. The wild-type Ki-ras transfectants lack functional TGF- receptors, whereas all three Ki-ras^G12V transfectants expressed functional TGF- receptors that bound ¹²⁵I-TGF-1. The previous studies showed that in cells with wild-type Ki-ras, TGF- receptors were not mutated, and receptor proteins were transported to the cell surface, but post-translational modification of TGF- receptor III (TRIII) was incomplete. We now show that the betaglycan form of TRIII is highly modified following translation when transiently expressed in Ki-ras^G12V cells, whereas no such post-translational modification of TRIII occurs in control cells. Antisense oligonucleotides directed to Ki-Ras decreased both TRIII post-translational modification in Ki-ras^G12V cells and TGF-1 down-regulation of p21, demonstrating the direct effect of mutant Ras. Therefore, one mechanism by which mutant Ki-Ras confers a more aggressive tumor phenotype is by enhancing TRIII post-translational modification.

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