Regulation of Cell Signaling and Adhesion

细胞信号传导和粘附的调节

• 批准号: 6973916
• 负责人: Joe William Ramos
• 金额: $ 11.17万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6973916
• 关键词: apoptosis; astrocytes; biological signal transduction; cell adhesion; cell growth regulation; cell migration; cell proliferation; confocal scanning microscopy; flow cytometry; gene expression; gene mutation; genetically modified animals; immunocytochemistry; laboratory mouse; leukocyte activation /transformation; messenger RNA; mitogen activated protein kinase; phosphoproteins; protein binding; protein protein interaction; protein structure function; spleen; thymus; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The Mitogen Activated Protein Kinase/ Extracellular signal Regulated Kinase (MAPK/ERK) cascade controls cell growth and survival and adhesion. I have used an expression-cloning strategy to isolate a protein that blocks ERK/MAPK (p42/p44) signaling, PEA-15. PEA-15 impairs several ERK functions such as activation of transcription. PEA-15 binds directly to ERK1/2 and co-localizes with it in the cytoplasm. While PEA-15 contains a death effector domain (DED) it affects apoptosis (programmed cell death) in only a subset of cell types, specifically some fibroblasts and astrocytes. In the PEA-15 null mouse, the most striking phenotype is a lymphoproliferative syndrome affecting both B and T cells. There is also a marked increase in hepatocyte proliferation and atrophy of the epidermis. PEA-15 maps to human chromosome 1q21. This is a gene rich locus implicated in a number of diseases, including acute myeloblastic leukemia and the skin disorder Ichthyosis vulgaris. PEA-15 has been cloned as a gene upregulated in patients with type II diabetes and appears to affect glucose metabolism in an undefined manner. Finally, the 3' untranslated region of PEA-15 has been cloned as a proto-oncogene, MAT-1, isolated from breast cancer cells. Hence, understanding the mechanism, of PEA-15 regulation of ERK signaling may have direct clinical relevance. The specific aims of this project are to: (1) Determine the residues of PEA-15 that are necessary for ERK binding by mutational analysis; (2) Determine the molecular mechanism by which PEA-15 affects ERK signaling; (3) Analyze the expression of PEA-15 mRNA and protein; and (4) Examine the function of PEA-15 expression on cell behavior in both cultured cells and cells derived from PEA-15 null mice. This work will illuminate the functional significance of PEA-15 and the molecular mechanism by which it acts. At the conclusion of these studies we will better understand how alterations in cell adhesion, migration, survival, and proliferation can be regulated by a novel player in cell signaling events. Moreover, this work will elucidate the potential role of PEA-15 in the pathogenesis of cancer and diabetes.

描述（由申请人提供）：有丝分裂激活的蛋白激酶/ 细胞外信号调节激酶（MAPK/ERK）级联控制细胞生长 以及生存和粘附。我已经使用了表达策略来 隔离蛋白质，该蛋白质阻断ERK/MAPK（P42/P44）信号传导，PEA-15。豌豆15 会损害几种ERK功能，例如转录的激活。豌豆15结合 直接到ERK1/2，并在细胞质中与其共定位。而豌豆15 包含一个死亡效应域（DED），它影响凋亡（程序性细胞） 死亡）仅在细胞类型的一部分中，特别是一些成纤维细胞和 星形胶质细胞。在Pea-15 null小鼠中，最引人注目的表型是 影响B和T细胞的淋巴增生性综合征。还有一个 表皮的肝细胞增殖和萎缩明显增加。 PEA-15地图至人类染色体1Q21。这是一个涉及的基因含量 包括急性骨髓白血病和皮肤疾病在内的疾病数量 鱼质福拉利。 PEA-15被克隆为患者上调的基因 患有II型糖尿病，似乎会影响不确定的葡萄糖代谢 方式。最后，豌豆15的3'未翻译区域被克隆为 从乳腺癌细胞中分离出的原始癌基因MAT-1。因此，理解 pea-15 ERK信号调节的机制可能具有直接的临床 关联。该项目的具体目的是：（1）确定残留物 通过突变分析所必需的PEA-15； （2） 确定PEA-15影响ERK信号传导的分子机制； （3） 分析PEA-15 mRNA和蛋白质的表达； （4）检查功能 培养细胞和衍生细胞中细胞行为的豌豆15表达 来自豌豆15无效的小鼠。这项工作将阐明 PEA-15及其作用的分子机制。在这些结束时 研究我们将更好地了解细胞粘附，迁移的改变， 生存和扩散可以由细胞中的新颖玩家调节 信号事件。此外，这项工作将阐明 PEA-15在癌症和糖尿病的发病机理中。