Role of the BMP SMADs in Oncogenesis

BMP SMAD 在肿瘤发生中的作用

• 批准号: 8091353
• 负责人: STEPHANIE A. PANGAS
• 金额: $ 35.44万
• 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/8091353
• 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; 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; Pattern; 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 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. 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.

描述（由申请人提供）：构成转化生长因子β (TGF?)家族的蛋白质具有广泛的发育和生理功能。各种TGF？家庭信号传导与癌症和包括生殖道疾病在内的其他疾病有关。TGF吗?家族可分为两个主要亚群：TGF？/激活素和骨形态发生蛋白（BMPs）。这两个亚群都使用SMAD途径作为典型的信号通路，但使用不同的亚型：SMAD2和SMAD3（称为AR-SMADs）信号用于TGF？而SMAD1、SMAD5和SMAD8（称为BR-SMADs）信号则负责bmp。我们已经建立了一个小鼠模型，在性腺体细胞中缺失Smad1和Smad5，这些小鼠发展为转移性性腺癌。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。本提案的总体目标是利用现有和新创建的小鼠模型来解剖BR-SMADs抑制肿瘤的机制，并在人颗粒细胞肿瘤的发病过程中检查这些相同的机制。体内和体外研究将用于分析br - smad在调节性腺和其他组织肿瘤形成方面的功能，特别是在控制基因表达方面。具体目的1和2利用研究TGF？以及BMP SMAD途径与小鼠和人类性腺肿瘤发生的关系。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。这些研究将明确BMP和TGF？配体与卵巢肿瘤的发生有关，并为理解癌症的发展产生关键的遗传模型。