1. Smad4 (Dpc4) in Colon Cancer Elizabeth Jarvis March 22, 2007

2. Objectives: • I. Cell Biological Role of Smad4 • II. Biological Role of Protein (What does it do for the Organism?) • III. Connection to Cancer • Colon and Pancreatic

3. I. Cell Biological Role of Smad4

4. Smads • Transcription Regulators • Different Classes- • Smad2 and 3: Phosphorylated at carboxyl-terminal serines • Smad4: co-Smad

5. Cellular Machinery • TGF-β = Serine/Threonine Kinase • Smad4 is NOT phosphorylated Fazhi Li, M.D. et al. (2005). World J. Surg. 29, 306-311.

6. How was this cell biological role determined? • Presence of Smad in MC-26 cell line→ Functioning TGF-β signaling pathway Fazhi Li, M.D. et al. (2005). World J. Surg. 29, 306-311.

7. How was this cell biological role determined? • Dominant Negative forms of Smads block TGF-β signaling Fazhi Li, M.D. et al. (2005). World J. Surg. 29, 306-311.

8. TGF/BMP Molecules Signal Through the SMADs Jonas Larsson and Stefan Karlsson. (2005). Oncogene.24, 5676−5692.

9. II. Biological Role of Protein What does it do for the Organism?

10. Disruption by Homologous Recombination • Embryonic lethal by day 7.5 • Defective mesoderm and visceral endoderm development in Smad4 mutant embryos Christian Sirard et al. (1998). Genes and Development. 12, 107-119.

11. Smad4 Gastrulation Defect • The gastrulation defect in Smad4 mutant embryos results from a defective visceral endoderm Christian Sirard et al. (1998). Genes and Development. 12, 107-119.

12. III. Connection to Cancer Colon and Pancreatic Cancer

13. Smad4 mutation in the progression of colorectal carcinogenesis Michiko Miyaki and Toshio Kuroki. (2003). Biochem and Biophysical Res. Comm. 306, 799-804.

14. Somatic mutations of the Smad4 gene detected in human cancer • Majority of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at MH2 Michiko Miyaki and Toshio Kuroki. (2003). Biochem and Biophysical Res. Comm. 306, 799-804.