ROLES OF PLEIOTROPHIN IN NORMAL AND ABNORMAL CELL GROWTH

多效素在正常和异常细胞生长中的作用

• 批准号: 2390859
• 负责人: Thomas F Deuel
• 金额: $ 28.64万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-10 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2390859
• 关键词: 3T3 cells; athymic mouse; binding proteins; breast neoplasms; cell growth regulation; cytokine; gene expression; gene interaction; genetically modified animals; heparin; mammary epithelium; molecular site; mouse mammary tumor virus; mutant; neoplasm /cancer genetics; neoplastic cell; neoplastic transformation; oncogenes; pathologic process; platelet derived growth factor; protein structure function; protooncogene; transforming growth factors; tumor promoters; tumor suppressor genes

Pleiotrophin (PTN) is a heparin-binding protein that functions as a weak mitogen with fibroblasts and brain capillary endothelial cells. It also induces process outgrowth and apparent differentiation with neuronal and glial progenitors. The ptn gene is a member of the platelet-derived growth factor (PDGF) induced early response cytokine genes and may mediate some of the normal functions of PDGF by autocrine or paracrine mechanisms. PTN also is transforming when its gene is overexpressed in NIH 3T3 cells. High levels of its expression have been found in mammary tumor cells and primary human breast tumors. Analysis of the functions of PTN in tumors thus may contribute to understanding both normal and abnormal cell growth. Furthermore, analysis of its ability to cooperate with other oncogenes offers a unique opportunity to study genetic pathways of tumorigenesis. Preliminary data are presented to establish that the PTN gene under control of the mouse mammary tumor virus (MMTV) promoter partially transforms mouse mammary epithelial cells. We plan to further study the potential of the ptn gene as a transforming gene in mouse mammary epithelial cells and as a transgene in mice. Its potential to cooperate with loss-of-function of tumor suppressor genes such as MMTV-p53 and gain-of-function of growth related genes such as MMTV-c-myc and MMTV-TGF- alpha to induce mammary tumors, and to enhance the aggressiveness of MMTV-c-neu induced mammary tumors in transgenic mice will be tested by cross-breeding MMTV-PTN mice with other MMTV-transgenic mice. It is also proposed to use mouse mammary epithelial cells to delineate functional (heparin binding, active site) domains of PTN that are required for its role in partial transformation by mutational analysis. The heparin binding mutants that are defined will be used to test the importance of binding of PTN to the extracellular matrix and/or cell surface for process outgrowth and in transformation. The active site mutants to be defined will be tested for loss of transforming potential in vitro, in the nude mouse, and for loss of ability to support process outgrowth of cells in cultures to determine if the same domaine mediates each of these activities. Appropriate functional mutants then will be expressed with MMTV in transgenic mice and tested alone and/or with cooperating genes by breeding to other MMTV transgenic mice. The results of this work will provide important new information on the functional roles of PTN, on its functional domains. It should direct strategies to alter the function of PTN in breast cancer and may advance understanding of the genetic basis of breast cancer in humans.

Pleiotroin(Ptn)是一种肝素结合蛋白，其功能是作为一种弱的 有丝分裂原与成纤维细胞和脑毛细血管内皮细胞。它还 诱导突起突起生长和与神经元和 神经胶质祖细胞。PTN基因是血小板源的一员。 生长因子(PDGF)诱导早期反应细胞因子基因并可能 通过自分泌或旁分泌调节PDGF的某些正常功能 机制。当PTN的基因过度表达时，它也在转化 NIH3T3细胞。在乳腺中发现了高水平的它的表达 肿瘤细胞和原发人类乳腺肿瘤。功能分析 因此，PTN在肿瘤中的研究可能有助于理解正常和 细胞生长异常。此外，对其合作能力的分析 为研究遗传基因提供了一个独特的机会 肿瘤发生的途径。 提供了初步的数据来证明PTN基因在 小鼠乳腺肿瘤病毒启动子的部分控制 转化小鼠乳腺上皮细胞。我们计划进一步研究 PTN基因作为小鼠乳腺转化基因的潜力 上皮细胞和小鼠的转基因。它的合作潜力 与MMTV-P53和MMTV-P53等肿瘤抑制基因功能丧失有关 生长相关基因如mmtv-c-myc和mmtv-cmyc的功能获得 α诱导乳腺肿瘤，并增强其侵袭性 MMTV-c-neu诱导的转基因小鼠乳腺肿瘤将通过 将MMTV-PTN小鼠与其他MMTV转基因小鼠杂交。 还建议使用小鼠乳腺上皮细胞来描绘 PTN的功能性(肝素结合，活性部位)结构域是 通过突变分析，它在部分转化中的作用是必需的。 定义的肝素结合突变体将用于测试 PTN与细胞外基质和/或细胞结合的重要性 用于加工外延和转化的表面。活动站点 将对待定义的突变体进行转化潜力损失测试 在体外，在裸鼠体内，并对失去支持过程的能力 细胞在培养物中的生长以确定是否相同的Domaine介导 这些活动中的每一个。合适的功能突变体将是 在转基因小鼠中表达MMTV，并单独和/或与 通过与其他MMTV转基因小鼠杂交来配合基因。结果是 这项工作将提供有关功能的重要新信息 PTN在其功能区中的作用。它应该将战略引导到 改变PTN在乳腺癌中的功能并可能增进对它的理解 人类乳腺癌的遗传基础。