BMP Receptor 1A Juvenile Polyposis Dayna Neo 3/21/13 Biol 445 001.

Presentation on theme: "BMP Receptor 1A Juvenile Polyposis Dayna Neo 3/21/13 Biol 445 001."— Presentation transcript:

1 BMP Receptor 1A Juvenile Polyposis Dayna Neo 3/21/13 Biol 445 001

2 Juvenile Polyposis is a rare autosomal dominant syndrome that increases your risk of intestinal tract cancer Humpath.com Juvenile Polyposis Daniel Calva, MD and James Howe, MD.

3 BMPR1A is a receptor serine/threonine kinase that phosphorylates SMAD transcription factors Hardwick, James C et al

4 BMPR1A is a tumor suppressor!!!!

5 BMP pathway inhibits proliferation by inhibiting the Wnt pathway BMP Pathway PTEN Wnt Cell Proliferation COX-2 expression EGF receptor

6 Two-hit hypothesis and loss of heterozygosity leads to Juvenile Polyposis Deletions, insertions, and missense/nonsense mutations  abnormally short, nonfunctional protein No mutations observed in transmembrane domain >90% penetrance Jyh-Cherng Yu and Chen Yang Shen

7 Individuals with juvenile polyposis have mutations in their BMPR1A James R. Howe et. al DE B S

8 Arrows represent bands corresponding to BMP1A mutations James R. Howe et. al Individual 12 will get JP D B E S

9 BMPR1A is present at the base of each intestinal crypt Hardwick, James C et al Crypt Villus

10 BMPR1A -/- lack the mesoderm layer during gastrulation Mishina Y et al

11 Treatments include polypectomy, prophylactic colectomy, and restorative proctocolectomy A subject of current investigation involves cycloxygenase inhibitors Cleavelandclinic.org

12 References Bessa, P.C et al, Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I(basic concepts). Journal of Tissue Engineering and Regenerative Medicine 2008:2:1-13 Hardwick, James C et al, Bone morphogenic protein signaling in colorectal cancer. Nature Reviews: Cancer 2008: 8: 806-812 Children’s Hospital Boston, 2009. JR Howe, et. al, Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nature. 2001 JR Howe, et.al, The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 2004, 41:484-491 Juvenile Polyposis : (SMAD4) Sequencing and Deletion/Duplication, (BMPR1A) Sequencing and Deletion/Duplication Kurland JE, et al, Cyclooxygenase-2 expression in polyps from a patient with juvenile polyposis syndrome with mutant BMPR1A. J Pediatr Gastroenterol Nutr. 2007, Mar;44(3):318-325 Lodewijk AA Brosens et, al. Juvenile polyposis syndrome. World Journal of Gastroenterology. Mishina, Y. et al, Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes, Dev. 1995. Genes & Development. Tian, Qiang et al, Bridging the BMP and Wnt Pathways by PI3 Kinase/Akt and 14-3-3. Landes Bioscience. Cell Cycle 4:2 215-216: February 2005.