BARC and kidney cancer

描述(申请人提供)：BARC(BMP拮抗剂在癌症中调节)是我们最近发现的一种新的BMP(骨形态发生蛋白)拮抗剂，作为寻找癌症中改变的分泌基因的一部分。BARC在肾癌中显著下调[在19/20个被测试的人类组织中]，与生长调节蛋白超家族具有序列相似性，并包含与胱氨酸结基序的完美序列匹配，该基序在已知结合和失活BMPs的蛋白质中发挥作用。此外，我们的初步数据显示，BARC的过度表达实质上抑制了肾癌细胞的生长。这一初步证据表明BARC参与了肾脏的生长调节，并提示BARC功能障碍可能与肾癌有关。本研究的假设是BARC在正常肾脏发挥生理性生长拮抗剂的作用，其下调可诱导肾上皮细胞增殖，这是肾脏肿瘤发生的重要前提。我们的具体目标是(1)通过条件表达、重组蛋白和shRNA来检测BARC在正常肾和肾癌生长调节中的作用；(2)通过SMAD报告分析和激活SMAD的免疫印迹来确定BARC抑制的生长调节信号转导通路；(3)通过免疫组织化学检测BARC在正常和恶性肾组织中的表达。尽管仍有许多工作要做，但我们的初步观察表明，BARC可能是一个新的肿瘤抑制基因--一个正常功能是抑制正常肾脏增殖的基因，它的缺失允许肾癌的发生。该方案中的实验将验证这一假说，并为BARC在肾癌预后和治疗中的潜在应用奠定基础。

DESCRIPTION (provided by applicant): 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.