Inhibition of the TGF-Beta Tumor Suppression Pathway Through Repression of Smad Dependent Transcription

摘要

Transforming growth factor-Beta (TGF Beta) inhibits the growth of normal mammary epithelial cells, but promotes invasiveness of malignant breast cancer cells. We have identified Ski and SnoN as negative regulators of TGF(3) signaling. The goal of this proposal is to understand the role of SnoN in breast carcinogenesis. The specific aims are: (1) To analyze the mechanism of Smad-induced degradation of SnoN. (2) To study the role of SnoN in breast carcinogenesis. We found that Smad3-induced degradation of SnoN requires the ubiquiflndependent proteasome and can be mediated by the anaphase promotmg complex (APC). Smad3 interacts with APC and SnoN, resulting in the recruitment of APC to SnoN and ubiquitination and degradation of SnoN. In breast cancer cells, this degradation pathway may be inactivated, leading to an elevated level of SnoN. When the small interference RNA was employed to reduce the expression of SnoN in malignant breast cancer cells, a restoration of responsiveness to TGF Beta-induced growth arrest and a marked decrease in the transforming activity of the breast cancer cells were observed. This suggests that an elevated level of SnoN indeed contributes to the malignant progression of breast cancer cells. Our studies have therefore identified an important factor affecting mammary carcinogenesis.