Smad4 (Dpc4) in Colon Cancer
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Transcript of Smad4 (Dpc4) in Colon Cancer
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.