The proposed research is based on the hypothesis that inhibition of the transforming growth factor beta (TGFbeta) signal transduction pathway can provide efficacious and specific intervention in some cancers. TGFbeta has been implicated in a broad variety of human diseases including cancer, immunoregulation, wound healing and tissue repair. In cancer, TGFbeta facilitates the progression and spread of tumor cells. The tumor-derived TGFbeta can aid tumorigenicity by direct actions on the cancer cell, by induction of angiogenesis, by local or systemic immunosuppression, and by alterations of stromal tissue that facilitate invasiveness. A chemical genetics approach is proposed to generate and characterize peptide aptamers that intervene in TGFbeta signaling. The working hypothesis is that selective perturbation of TGFbeta responses may be achieved by understanding the specific interactions of phosphorylated Smad (Smad-P) complexes with other proteins and that selective intervention strategies are possible by interfering with a specific subset of Smad-P's interactions.
The specific aims i nclude the use of fifteen known Smad interaction motifs to generate peptide aptamers that perturb specific responses to TGFbeta signal transduction, characterization of the solution binding properties of the aptamers, structure-function analysis by directed and random mutagenesis and expression of the aptamers in cells to evaluate their effects on Mediated-mediated gene expression. The proposed research will provide new strategies and reagents for perturbing the Mediated signaling pathway, for identifying target interactions that may be important in specific pathological states, and for identifying structures that are good ligands for Smad-P.
| Das, Shreyas; Becker, Bryan N; Hoffmann, F Michael et al. (2009) Complete reversal of epithelial to mesenchymal transition requires inhibition of both ZEB expression and the Rho pathway. BMC Cell Biol 10:94 |
| Lim, S Kyun; Hoffmann, F Michael (2006) Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF-beta signaling. Proc Natl Acad Sci U S A 103:18580-5 |
| Zhao, Bryan M; Hoffmann, F Michael (2006) Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. Mol Biol Cell 17:3819-31 |
| Cui, Qiqi; Lim, Sang Kyun; Zhao, Bryan et al. (2005) Selective inhibition of TGF-beta responsive genes by Smad-interacting peptide aptamers from FoxH1, Lef1 and CBP. Oncogene 24:3864-74 |
