1. BMP Receptor 1 : Juvenile Polyposis (Colon Cancer) Cecily Johnson Biology 169 March 24, 2005

2. Juvenile Polyposis Syndrome What is JPS? A neoplastic (proliferative) vascular disorder. Predisposes individuals to gatrointestinal cancers. Source: http://www.gihealth....on/photo/colonPolyps.htmlhttp://www.gihealth....on/photo/colonPolyps.html

3. How is it inherited? JPS can occur in an individual by a brand new gene change. By a gene change that is inherit from a parent (at least half of reported cases). JPS is inherited in an autosomal dominant fashion. All contents copyright © 1992-2004 the Author(s) and The University of Iowa. All rights reserved. http://www.vh.org/pediatric/patient/cancercenter/juvenilepolyposis/inherited.ht ml

4. How is it Related to cancer? Class notes

5. TGF-Beta Pathway

6. Normal Function of TGF-Beta Pathway: Pathway product (SMAD4) binds to DNA in the nucleus and regulates transcription of target genes. Very important in majority of body cells In cardiovascular development, and remodeling and growth control of body cells. Nature Reviews: Genetics,FROM DEVELOPMENTAL DISORDER TO HERITABLE CANCER: IT’S ALL IN THE BMP/TGF-β FAMILY, Kristin A.Waite* and Charis Eng*‡§. October 2003 Volume 4

7. BMP Specific Functions Important in cell differentiation Regulate proliferation, and apoptosis Nature Reviews: Genetics,FROM DEVELOPMENTAL DISORDER TO HERITABLE CANCER: IT’S ALL IN THE BMP/TGF-β FAMILY, Kristin A.Waite* and Charis Eng*‡§. October 2003 Volume 4

8. BMPR1A Activation of this receptor by the Type II receptors results in activation of the R-SMADs. (Just another step in the pathway) JPS individuals with BMPR1A mutations have 10 or more gastrointestinal tract polyps and a family history of gastrointestinal cancer.

9. Mutations in BMPR1A Inherited Cancers: Associated with 50% of JPS cases. Mutations are frequent in the ligand-binding domain and the kinase domain, resulting in a loss of ligand binding or loss of kinase activity. Truncating mutations. Nature Reviews: Genetics,FROM DEVELOPMENTAL DISORDER TO HERITABLE CANCER: IT’S ALL IN THE BMP/TGF-β FAMILY, Kristin A.Waite* and Charis Eng*‡§. October 2003 Volume 4

10. Mutations in BMPR1A Non-inherited Cancers: Associated with 50% of JPS individuals. Due to large deletions and rearrangements or promoter mutations in one of the genes. Other reasons could be due in part to mutations in one of the other Transformation Growth Factor-Beta Pathway members.

11. Knock Out Null mutations of Bmpr1a are lethal to mice embryos. Generated mice in which Bmpr1a could be conditionally inactivated for study.

12. Knock Out: Results Disruption of homeostasis of intestinal epithelial regeneration. Eventually leading to intestinal polyposis much like those in human JPS. http://www.iecdesmoines.com/images/polyp2.jpg

13. More Knock Out Results In wild-type mice, proliferation cells are located in the upper crypt region. In mutant mice, the proliferating cell population was expanded.

14. ANY QUESTIONS?