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SMAD4/DPC4: A Tumor Suppressor James Brooks March 23rd, 2006 Found on chromosome 18 in humans, encodes 11 exons A 552 amino acid protein found in the cytoplasm SMAD Structure: MH1 and MH2 Domains SMAD proteins exist as homo-oligomers • The quaternary structure of SMADs consists of three monomers attached at their MH2 domains (homo-oligomers) • MH2 domains are also responsible for heterooligomerization SMAD4 is expressed at all stages of development Above: Northern blot (RNA) of SMAD4 (3.8 kb) at various stages of development in mouse (L32 is a loading control) SMAD4 mutant mouse embryos exhibit early embryonic lethality • By day 6.5, SMAD4 mutant mouse embryos appear much smaller than wild type ones; the difference in size is attributed to reduced cell proliferation • By day 7.5, SMAD4 mutant mouse embryos are lethal SMAD4 is the convergence point of several TGF-β pathways SMAD4 activity regulates cell proliferation in the TGF-β signaling pathway Left: SMAD4 distribution in absence of TGF-β Right: SMAD4 after translocation into nucleus following stimulation by TGF-β SMAD4 activity regulates cell proliferation in the TGF-β signaling pathway The Smad4 gene is often mutated in the MH2 domain Familial Juvenile Polyposis (FJP) • • • • Clinical manifestation of germline SMAD4 mutation, phenotypically similar to that of familial adenomatous polyposis (FAP) from loss of APC function Autosomal Dominant inheritance pattern SMAD4 is mutated in approximately 50% of FJP cases Agrees with Knudson’s two-hit model Above: A juvenile polyp Smad4 mutation is often seen in late-stage malignancies that have metastasized This makes sense! To sum things up… • SMAD4 is a tumor suppressor that regulates cell proliferation through interaction with transcription factors • When inactive, it is located in the cytosol. It is translocated into the nucleus once activated • Loss of SMAD4 is associated with familial juvenile polyposis, and is often absent in malignant pancreatic and colon carcinomas References • • • • • • • • • Karyotype: http://www.amnh.org/learn/musings/FA01/ia/HW_01.jpg SMAD4 Crystal Structure: Shi et. al. A structural basis for the mutational inactivation of the tumour suppressor Smad4. 3 Jul 1997. Nature. SMAD MH1 and MH2 Domain Structure: http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/roth/discussion.html Smad Mediated TGF-Beta Signaling Pathway: Miyaki et. al. Role of Smad4 (DPC4) inactivation in human cancer. 2003. Biochemical and Biophysical Research Communications. Smad4 Northern Blot: Sirard et. al. The tumor suppressor gene Smad4/DPC4 is required for gastrulation and later for anterior development of the mouse embryo. 1998. Genes and Development. Wild-type and Smad Mutant embryos: Sirard et. al. The tumor suppressor gene Smad4/DPC4 is required for gastrulation and later for anterior development of the mouse embryo. 1998. Genes and Development. TGF-Beta Superfamily Signaling Pathway: Waite and Eng. From developmental disorder to heritable cancer: it’s all in the BMP/TGF-β family. 2003. Nature. TGF-Beta Signaling Pathway: Lodish et. al. Molecular Cell Biology p. 957 SMAD4 Localization Photos: http://biochemistry.utoronto.ca/research/signal_transduction_and_regulation.html References, Continued • • • Mutations in SMAD4: Miyaki et. al. Role of Smad4 (DPC4) inactivation in human cancer. 2003. Biochemical and Biophysical Research Communications. Juvenile Polyp: http://www.surgery.uiowa.edu/surgery/physpubs/familialjuvenilepolyposis.html SMAD4 in Cancer: Miyaki et. al. Role of Smad4 (DPC4) inactivation in human cancer. 2003. Biochemical and Biophysical Research Communications.