Functional Analysis of SMAD Activation in TGF-B-mediated Negative Growth Control in Breast Epithelial Cells

摘要

Transforming growth factor-beta (TGF-beta) is a potent growth inhibitory polypeptide hormone. Although the loss of this negative proliferative signal is often seen in the deregulated growth of early cancer formation, the TGF-beta mediated intracellular pathways that control cell growth remain largely unknown. We propose three aims to (1) elucidate the functional role of Smads in TGF-beta signaling; (2) assess their contribution in regulating cell proliferation; and (3) to provide evidence that Smad3 acts in vivo as a tumor suppressor of early breast cancer formation. In the first year of funding, we have provided evidence that the Smads are specific sequence DNA-binding proteins, and functionally interact with other transcription factors and the p300/CBP coactivator family of proteins to coordinate disparate pathways in the regulation of specific genes. Towards the goal of the second aim, we demonstrated that Smad3 is an essential component of TGF-3 mediated growth inhibition in fibroblasts and epithelial cells, and that cyclin Dl and c-Myc are Smad3 dependent TGF-beta repressible target genes. The last aim to evidence that Smad3 may be an in vivo tumor suppressor will be completed with the use of the Smad3 null mouse model, carcinogen treatment and crossing into the APCmin mouse background.