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

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

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

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

TGFβ Pathway Miyaki and Kuroki (2003)

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

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

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)

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

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

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

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)

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

Clinical Implications Colon Cancer Screenings SDI Diagnostic Imaging (2005)