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ZAFIA ANKLESARIA Role of BMPR1A in Juvenile Polyposis Syndrome Biology 169 THE DISCOVERIES BEGIN…. What is juvenile polyposis syndrome? Autosomal dominant inherited syndrome with variable penetrance Presence of juvenile polyps in the gastrointestinal tract Increased intestinal crypt formation and increased intestinal stem cell number. Congenital defects such as pulmonary valve stenosis Gastrointestinal cancer predisposition with a malignant potential Symptoms include… Severe recurrent diarrhea Rectal bleeding Intussusception Anemia Prolapse Abdominal pain Where and When 1/100000 -1/160000 Malignancy potential of 65% Extra intestinal cancers are not common Age of diagnosis 26.1 + 15.6 years Clinical similarity to other polyposis syndromes - Cowdens syndrome - Peutz-Jeghers syndrome - Bannayan-Riley-Ruvalcaba syndrome And of course…HOW Mutations in SMAD4 23% Mutations in BMPR1A 25 % The other 50% have UNKNOWN mutations My focus : BMPR1A Bone Morphogenic Protein Receptor Type IA Serine Threonine Kinase Receptor Receptor for the Bone Morphogenic Protein ligand Phosphorylates downstream SMADS Signaling controls duplication of intestinal stem cells and restricts crypt number Tumor Suppressor gene ( surprised ?) PATHWAY BMP Cell membrane BPMPR2 SMAD4 P BMPR1A P P RSMAD P Nuclear membrane DNA binding & Down regulation of growth Transcription & Apoptosis PATHWAY BMP ligand binds to the type I – type II receptor complex Receptors oligomerize and BMPR2 phosphorylates and activates BMPR1A BMPR1A phosphorylates R SMADS R SMADS hetero- oligomerize with Co SMAD (SMAD4) Complex migrates to the nucleus Transcribe genes that down regulate growth and promotes apoptosis Therefore…. Normal BMP signaling reduces cell Proliferation….so BMPR1A is a TUMOR SUPPRESSOR When a tumor suppressor gets mutated we get tumors Mutations BMPR1A mutations cause : Formation of juvenile polyps in the GI tract due to excess intestinal stem cells and crypt formation The polyps cause the diagnostic symptoms of the syndrome Predisposition to cancers of the GI tract, due to loss of tumor suppression properties The GENE Receptor for ligands of the TGF-β super-family 11 exons encoding : Signal peptide Extracellular ligand binding domain Transmembrane domain Kinase domain ATP binding domain Most mutations are missense but a few are truncating Most mutations occur in the kinase domain Other players in the pathway… Noggin – A BMP antagonist PTEN - BMP signaling enhances PTEN activity PTEN is a major Tumor Suppressor Other players… BMPNOG Cell membrane BPMPR2 P BMPR1A R-SMAD PTEN SMAD4 Nuclear membrane BMPNOG Cell membrane BPMPR2 P BMPR1A R-SMAD PTEN SMAD4 Nuclear membrane ROLE OF BMPR1A Critical role in endodermal morphogenesis and ectodermal patterning : - homozygous mutant mouse fails to gastrulate - mosaic embryos have a convolution of the ectoderm, distorted anterior end, and form no heart Important role in intestinal growth control: - conditional inactivation in the intestine of mice leads to the formation of juvenile polyps - conditional misexpression of noggin in the intestine leads to ectopic crypt formation and large polyps Therefore…. BMPR1A is : A regulator of morphogenesis congenital defects A suppressor of crypt formation and regulates intestinal growth Intestinal Polyps A tumor suppressor, regulator of PTEN Predisposition to cancers TREATMENTS Routine colonoscopy Endoscopic polypectomy to reduce bleeding and intestinal obstruction Colectomy may be necessary Regular screening for cancers Now we know… (quite a bit) References Batts, L. E., et al. "Bmp Signaling is Required for Intestinal Growth and Morphogenesis." Developmental dynamics : an official publication of the American Association of Anatomists (2006) Chow, E., and F. Macrae. "A Review of Juvenile Polyposis Syndrome." Journal of gastroenterology and hepatology 20.11 (2005): 1634-40. Haramis, A. P., et al. "De Novo Crypt Formation and Juvenile Polyposis on BMP Inhibition in Mouse Intestine." Science 303.5664 (2004): 1684-6. Sayed, M. G., et al. "Germline SMAD4 Or BMPR1A Mutations and Phenotype of Juvenile Polyposis." Annals of Surgical Oncology : The Official Journal of the Society of Surgical Oncology 9.9 (2002): 901-6. Tian, Q., et al. "Bridging the BMP and Wnt Pathways by PI3 kinase/Akt and 14-3-3zeta." Cell.Cycle 4.2 (2005): 215-6.