zafia anklesaria role of bmpr1a in juvenile polyposis syndrome biology 169
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TRANSCRIPT
ZAFIA ANKLESARIA
Role of BMPR1A in JuvenilePolyposis 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
P
BMP
BPMPR2 BMPR1A
SMAD4
PP
P
RSMAD
DNA binding & Down regulation of growth Transcription & Apoptosis
Nuclear membrane
Cell membrane
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…
P
BMP
BPMPR2 BMPR1A
PTEN
NOG
R-SMAD
SMAD4
Cell membrane
Nuclear membrane
P
BMP
BPMPR2 BMPR1A
PTEN
NOG
R-SMAD
SMAD4
Cell membrane
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)
ReferencesBatts, 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.