Smad4 (Dpc4) in Colon Cancer

Elizabeth Jarvis

March 22, 2007

Objectives:

I. Cell Biological Role of Smad4

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

III. Connection to CancerColon and Pancreatic

I. Cell Biological Role of Smad4

Smads

Transcription RegulatorsDifferent Classes-

Smad2 and 3: Phosphorylated at carboxyl-terminal serines

Smad4: co-Smad

Cellular Machinery

TGF-β = Serine/Threonine Kinase

Smad4 is NOT phosphorylated

Fazhi Li, M.D. et al. (2005). World J. Surg. 29, 306-311.

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.

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.

TGF/BMP Molecules Signal Through the SMADs

Jonas Larsson and Stefan Karlsson. (2005). Oncogene. 24, 5676−5692.

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

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.

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.

III. Connection to Cancer

Colon and Pancreatic Cancer

Smad4 mutation in the progression of colorectal carcinogenesis

Michiko Miyaki and Toshio Kuroki. (2003). Biochem and Biophysical Res. Comm. 306, 799-804.

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.