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Oncogene. 2003 Jun 12;22(24):3698-711.

Attenuation of the TGF-beta-Smad signaling pathway in pancreatic tumor cells confers resistance to TGF-beta-induced growth arrest.

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Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, UK.


We have investigated the mechanism whereby tumor cells become resistant to the antiproliferative effects of transforming growth factor (TGF)-beta, while maintaining other responses that can lead to increased malignancy and invasiveness. TGF-beta signaling results in nuclear accumulation of active Smad complexes which regulate transcription of target genes. Here we show that in two pancreatic carcinoma cell lines, PT45 and Panc-1, that are resistant to TGF-beta-induced growth arrest, the TGF-beta-Smad signaling pathway is attenuated compared with epithelial cells that are sensitive to the antiproliferative effects of TGF-beta (HaCaT and Colo-357). In PT45 and Panc-1 cells, active Smad complexes remain nuclear for only 1-2 h compared with more than 6 h in HaCaT and Colo-357 cells. The attenuated pathway in PT45 and Panc-1 cells correlates with low levels of TGF-beta type I receptor and results in an altered expression profile of TGF-beta-inducible genes required for cell cycle arrest. Most significantly, expression of the CDK inhibitor, p21(Cip1/WAF1), which is required for TGF-beta-induced growth arrest in these cells, is not maintained. Moreover, we show that artificially attenuating the TGF-beta-Smad signaling pathway in HaCaT cells is sufficient to prevent TGF-beta-induced growth arrest. Our results demonstrate that the duration of TGF-beta-Smad signaling is a critical determinant of the specificity of the TGF-beta response.

[Indexed for MEDLINE]

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