Role of the BMP SMADs in Oncogenesis

性状（由申请方提供）：包含转化生长因子β（TGF？）的蛋白质家庭具有广泛的发育和生理功能。各种TGF？家族信号传递与癌症和其他疾病，包括生殖道疾病有关。TGF？家族可分为两个主要亚组：TGF？/激活素和骨形态发生蛋白（BMP）。这两个亚组使用SMAD途径作为经典信号传导途径，但利用不同的亚型：SMAD 2和SMAD 3（称为AR-SMADs）信号转化生长因子？和激活素，而SMAD 1，SMAD 5和SMAD 8（称为BR-SMAD）则是BMP的信号。我们已经开发了一种小鼠模型，用于在性腺的体细胞中缺失Smad 1和Smad 5，这些小鼠发生转移性性腺癌。虽然我们的初步数据清楚地表明BR-SMADs在肿瘤抑制中的作用，但肿瘤发生和转移发展背后的机制尚不清楚。该提案的总体目标是使用现有和新创建的小鼠模型剖析BR-SMAD抑制肿瘤的机制，并在人类颗粒细胞肿瘤的发病机制中检查这些相同的机制。体内和体外研究都将用于分析BR-SMAD在调节性腺和其他组织中肿瘤形成中的功能，特别是关于基因表达的控制。具体目标1和2利用研究TGF？和BMP SMAD途径，因为它们与小鼠和人类的性腺肿瘤发生有关。第三个目的是研究BR-SMADs作为肿瘤血管生成调节因子的作用。这些研究将确定BMP和TGF？配体，因为它们与卵巢中的肿瘤发生有关，并为理解癌症的发展产生关键的遗传模型。 公共卫生相关性：发育信号通路在癌症中经常被错误调节。新的小鼠模型已经揭示了骨形态发生途径在调节性腺癌中的新作用，尽管该模型中肿瘤和转移形成背后的机制尚不清楚。了解SMAD通路如何控制正常和病理组织中的细胞生长和分化，将使我们能够了解人类癌症中这一信号通路的遗传中断，以及基于对TGF？家庭途径。

DESCRIPTION (provided by applicant): The proteins that comprise the transforming growth factor beta (TGF?) family have wide-ranging developmental and physiologic functions. Dysregulation of various TGF? family signaling has been linked to cancer and other diseases including those of the reproductive tract. The TGF? family can be divided into two main subgroups: the TGF?/activins and the bone morphogenetic proteins (BMPs). Both subgroups use the SMAD pathway as the canonical signaling pathway, but utilize different isoforms: SMAD2 and SMAD3 (called the AR-SMADs) signal for TGF? and activin, while SMAD1, SMAD5, and SMAD8 (called the BR-SMADs) signal for the BMPs. We have developed a mouse model for deletion of Smad1 and Smad5 in the somatic cells of the gonad and these mice develop metastatic gonadal cancers. While our preliminary data clearly indicate a role for the BR-SMADs in tumor suppression, the mechanism behind tumorigenesis and metastasis development is unknown. The overall goal of this proposal is to dissect the mechanism behind tumor suppression by the BR-SMADs using existing and newly-created mouse models, and to examine these same mechanisms during the pathogenesis of human granulosa cell tumors. Both in vivo and in vitro studies will be used to analyze the function of the BR-SMADs in regulating tumor formation in the gonad and other tissues, particularly with respect to control of gene expression. Specific Aims 1 and 2 utilize study the interrelationship between the TGF? and BMP SMAD pathways as they relate to gonadal tumorigenesis in mice and humans. The third aim investigates the role of the BR-SMADs as regulators of tumor angiogenesis. These studies will define essential roles for the BMP and TGF? ligands as they relate to oncogenesis in the ovary and generate key genetic models for understanding the development of cancer. PUBLIC HEALTH RELEVANCE: Developmental signaling pathways are often misregulated in cancer. New mouse models have uncovered a novel role for the bone morphogenetic pathway in regulating gonadal cancer, although the mechanism behind tumor and metastasis formation in this model is unclear. Understanding how the SMAD pathway controls cell growth and differentiation in normal and pathologic tissues will allow us understand genetic disruptions in this signaling pathway in human cancers, as well as to tailor diagnostics and treatment regimes based on a molecular understanding of the TGF? family pathway.