Colon cancer is one of the leading causes of mortality in western countries. Whereas much progress has been made to date, in a significant number of cases the molecular mechanisms underlying the initiation of the disease and its progression remain unknown. Bamacan is a newly described chondroitin sulfate proteoglycan that abounds in basement membranes and is also found in the cell nucleus. The applicant recently cloned and characterized the bamacan gene and found that its expression is significantly increased in approx. 70 percent of human colon carcinomas. Aberrant bamacan was also detected in five human colon carcinoma cell lines and in neoplastic tissue of APC Min/+ mice that lack a functional APC tumor suppressor and develop intestinal tumors. Overexpression of bamacan in normal fibroblasts causes transformation, including formation of foci, acquisition of anchorage independent growth and loss of contact inhibition. Bamacan belongs to the Structural Maintenance of Chromosome (SMC) family of proteins and is involved in DNA repair and in the ordered separation of sister chromatids. Alteration of these processes leads to genetic instability and aneuploidy, conditions that can initiate the tumorigenic process. A hypothesis of the proposal is that deregulated expression of bamacan is either initiating transformation or is a secondary event that is necessary for the clonal propagation of the neoplastic cells. A long-term research objective is to elucidate the role of bamacan in the establishment and maintenance of a transformed phenotype. This revised grant proposes to investigate: 1) The transcriptional regulation of the bamacan gene. 2) The functional role of bamacan in tumorigenesis by altering its expression and by assessing the effect of protein mutation using a dominant-negative approach. 3) The contribution of bamacan in vivo to colon tumorigenesis by generating transgenic mice over-expressing bamacan in the intestinal epithelium.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA082290-02S1
Application #
6572445
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Rosenfeld, Bobby
Project Start
2001-02-01
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$16,300
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Ghiselli, Giancarlo (2006) SMC3 knockdown triggers genomic instability and p53-dependent apoptosis in human and zebrafish cells. Mol Cancer 5:52
Ghiselli, Giancarlo; Agrawal, Amit (2005) The human D-glucuronyl C5-epimerase gene is transcriptionally activated through the beta-catenin-TCF4 pathway. Biochem J 390:493-9
Patel, Chirag A; Ghiselli, Giancarlo (2005) The RET finger protein interacts with the hinge region of SMC3. Biochem Biophys Res Commun 330:333-40
Ghiselli, Giancarlo; Liu, Chang-Gong (2005) Global gene expression profiling of cells overexpressing SMC3. Mol Cancer 4:34
Ghiselli, Giancarlo; Farber, Steven A (2005) D-glucuronyl C5-epimerase acts in dorso-ventral axis formation in zebrafish. BMC Dev Biol 5:19
Patel, Chirag A; Ghiselli, Giancarlo (2005) Hinderin, a five-domains protein including coiled-coil motifs that binds to SMC3. BMC Cell Biol 6:3
Ghiselli, Giancarlo; Coffee, Nefeteria; Munnery, Christine E et al. (2003) The cohesin SMC3 is a target the for beta-catenin/TCF4 transactivation pathway. J Biol Chem 278:20259-67