BARC (BMP Antagonist Regulated in Cancer) is a novel BMP (bone morphogenic protein) antagonist we recently discovered as part of a search for secretory genes altered in cancer. BARC is strikingly downregulated in kidney cancers [in 19/20 human tissues tested], has sequence similarity to a superfamily of growth regulatory proteins, and contains a perfect sequence match for a cystine knot motif that functions in proteins known to bind and inactivate BMPs. Further, our preliminary data show that overexpression of BARC substantially inhibits kidney cancer cell growth. This preliminary evidence points to the involvement of BARC in growth regulation of the kidney, and suggests that BARC dysfunction may be associated with kidney cancer. The hypothesis to be tested in this proposal is that BARC functions as a physiologic growth antagonist in the normal kidney, and that its down-regulation induces proliferation in kidney epithelium, an important prerequisite for renal oncogenesis.
Our Specific Aims are to (1) Test the role of BARC in growth regulation of normal kidney and kidney cancer using conditional expression, recombinant protein, and shRNA; (2) Identify growth-regulatory signal transduction pathways inhibited by BARC using SMAD reporter assays and immunoblots for activated SMAD; (3) Assess expression of BARC in normal and malignant kidney tissue using immunonhistochemistry. Although much remains to be accomplished, our preliminary observations thus far suggests that BARC may be a novel tumor suppressor gene - a gene whose normal function is to suppress proliferation in the normal kidney, and whose absence is permissive for kidney cancer development. The experiments in this proposal will test this hypothesis, and lay the groundwork for the potential use of BARC in kidney cancer prognosis and therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA119181-01
Application #
6961548
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Yassin, Rihab R,
Project Start
2005-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$115,928
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Clausen, Kathryn A; Blish, Kimberly R; Birse, Charles E et al. (2011) SOSTDC1 differentially modulates Smad and beta-catenin activation and is down-regulated in breast cancer. Breast Cancer Res Treat 129:737-46
Blish, Kimberly R; Clausen, Kathryn A; Hawkins, Gregory A et al. (2010) Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors. J Exp Clin Cancer Res 29:147
Turk, Tamara; Leeuwis, Jan Willem; Gray, Julia et al. (2009) BMP signaling and podocyte markers are decreased in human diabetic nephropathy in association with CTGF overexpression. J Histochem Cytochem 57:623-31
Blish, Kimberly Rose; Wang, Wei; Willingham, Mark C et al. (2008) A human bone morphogenetic protein antagonist is down-regulated in renal cancer. Mol Biol Cell 19:457-64