Activin is a growth suppressive ligand of the TGF2 superfamily. It initiates its signaling via a specific receptor, activin receptor 2 (ACVR2), that subsequently phosphorylates activin receptor 1 (ACVR1) to activate a signaling cascade culminating in nuclear translocation of SMAD proteins. We can show that ACVR2 protein is lost by distinct mechanisms in human colon cancer regardless of the type of genomic instability and is associated with an increase in tumor size and grade in primary colon cancer specimens. Further, abrogated activin signaling is associated with loss of growth control mediated by the protein p21waf1, which slows the cell cycle. The goal of this project is to analyze the effects of loss of ACVR2 in intestinal tumorigenesis utilizing two mouse models. We hypothesize that mutated ACVR2 interrupts activin signaling causing increased intestinal cancer growth. We will first assess colon neoplasia rates and tumor size in ACVR2-deficient mice following chemical challenge with the known carcinogen azoxymethane. Then, the observed tumors will be analyzed for markers of proliferation and cell death and p21waf1 expression. Second, ACVR2-deficent [sic] mice will be crossbred with APCmin mice, who develop intestinal adenomas and cancers at an early age. We will compare tumor size and number in the crossbred mice versus control APCmin mice. Histological grade assessment of the tumors will be performed, as well as determination of phosphorylated SMAD2, proliferation, cell death, and p21waf1 expression. This project assesses the role of activin signaling and ACVR2 using in vivo models to validate its suspected role in intestinal neoplasia. ? Project Narrative/Relevance Colon cancer is the second deadliest cancer in the US. Understanding the genetic mechanisms of how colon cancer forms will help to develop better tools to prevent, diagnose, and treat colon cancer. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK081566-01
Application #
7510556
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2008-08-05
Project End
2010-06-30
Budget Start
2008-08-05
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$77,250
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sporn, Judith C; Hothorn, Torsten; Jung, Barbara (2011) BARD1 expression predicts outcome in colon cancer. Clin Cancer Res 17:5451-62