Role of the BMP SMADs in Oncogenesis

BMP SMAD 在肿瘤发生中的作用

• 批准号: 8403720
• 负责人: STEPHANIE A. PANGAS
• 金额: $ 33.31万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403720
• 关键词: Activins; Address; Adolescent; Adult; Alleles; BMP7 gene; Bone Morphogenetic Proteins; Cell Differentiation process; Cell Proliferation; Cells; Colorectal Neoplasms; Data; Development; Developmental Process; Diagnostic; Disease; Embryo; Family; Female; Future Generations; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Goals; Gonadal structure; Growth Factor; Human; In Vitro; Knock-out; Knockout Mice; Knowledge; Lead; Ligands; Link; Lymphatic Metastasis; MADH2 gene; MADH3 gene; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Ovarian Follicle; Ovary; Pancreatic carcinoma; Pathogenesis; Pathologic; Pathway interactions; Peritoneal; Phenotype; Physiological; Physiological Processes; Platelet-Derived Growth Factor; Play; Property; Protein Family; Protein Isoforms; Proteins; Role; Sex Cord-Gonadal Stromal Tumors; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Somatic Cell; Somatic Mutation; Subgroup; Testing; Testis; Tissues; Transcriptional Regulation; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Angiogenesis; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Up-Regulation; Work; aged; angiogenesis; arm; base; bone; cell growth; cell type; gonadal cancer; granulosa cell; granulosa cell tumor; human disease; in vivo; leydig interstitial cell; male; mouse model; mutant; neoplastic cell; neovascularization; novel; novel diagnostics; null mutation; promoter; protein function; public health relevance; recombinase; reproductive; sertoli cell; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

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.

描述(申请人提供)：构成转化生长因子β(TGF？)的蛋白质家庭具有广泛的发育和生理功能。多种转化生长因子的失调？家庭信号与癌症和包括生殖道疾病在内的其他疾病有关。转化生长因子？骨形态发生蛋白家族主要分为两个亚类：转化生长因子β/激活素和骨形态发生蛋白。这两个亚组都使用SMAD通路作为典型的信号通路，但使用不同的亚型：Smad2和Smad3(称为AR-Smads)信号与转化生长因子？和激活素，而Smad1、Smad5和Smad8(称为BR-SMADS)信号用于BMP。我们已经建立了一种在性腺的体细胞中缺失Smad1和Smad5的小鼠模型，这些小鼠发生了转移性性腺癌。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。这项建议的总体目标是利用现有的和新创建的小鼠模型来剖析BR-SMADS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。体内和体外研究将被用来分析BR-Smads在调节性腺和其他组织中的肿瘤形成方面的功能，特别是在控制基因表达方面。利用特异靶1和特异靶2研究转化生长因子和转化生长因子的相互关系。和BMP SMAD通路，因为它们与小鼠和人类性腺肿瘤的发生有关。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。这些研究将确定骨形态发生蛋白和转化生长因子的基本作用？配体与卵巢中的肿瘤发生有关，并产生关键的遗传模型以了解癌症的发展。