1. The Role of SMAD4 (DPC4) in Cancer
Lauren Kirkpatrick
March 18, 2008

2. Overview Tumor-suppressor gene
Involved in pancreatic and colon cancers
Part of the TGFβ signaling pathway
Required for embryonic development

3. SMAD4 Protein MH1 Domain: DNA binding
MH2 Domain: oligodimerization, transcriptional activation, and nuclear localization
European Molecular Biology Organization(2000)

4. Smad4 is Widely Expressed in Embryonic and Adult Tissues
Northern Blot Analysis
Sirard et al. (1997)

5. TGFβ Pathway
Miyaki and Kuroki (2003)

6. TGFβ Family
Smad4 involved in multiple pathways
Waite and Eng (2003)

7. Discovery in Model Organisms
SMADs identified by homology to Drosophila Mothers Against Decapentaplegic
3 Mad homologs in C. elegans
Sma-2, sma-3, and sma-4
Referred to as SMADs in vertebrates

8. Knockout Mice Homozygotes: embryonic lethal (by day 7.5) Reduced size
Failed to gastrulate
Did not make mesoderm or primitive streak
Sirard et al. (1997)

9. Knockout Mice Heterozygotes: normal up to ~1 year Up to 11 months:
No increase in tumorigenecity
Eventually developed gastric and duodenal polyps

10. Mutations in Human Cancers
Most mutations occur in the MH2 region
Encode the C-terminal half of the gene
Miyaki and Kuroki (2003)

11. Familial Juvenile Polyposis
Autosomal Dominant Inheritance
May be accompanied by other symptoms
Waite and Eng (2003)

12. Double Knockout Mice
Mutant mice with APC gene and Smad4 gene on same chromosome
Meiotic recombination
Compared APC(+/-), smad4(+/-) mice with APC(+/-), smad4(+/+)
Double Heterozygotes:
Larger Polyps
Submucosal invasion
Dept. of Biology, Davidson College (2005)

13. SMAD4 Involved in Advanced Cancer Progression
The frequency of SMAD4 mutation increases with increasing level of severity of cancer
Miyaki and Kuroki (2003)

14. Clinical Implications
Colon Cancer Screenings
SDI Diagnostic Imaging (2005)