SIGNALING IN LIVING CELLS

活细胞中的信号传导

• 批准号: 8410116
• 负责人: NARASIMHAN GAUTAM
• 金额: $ 30.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410116
• 关键词: A549; Address; Biological Models; Bradykinin Receptor; Cancerous; Carcinoma; Cathepsins; Cell Aging; Cell division; Cell membrane; Cell secretion; Cells; Cellular Stress; Complex; Cues; Diabetes Mellitus; Disease; Endoplasmic Reticulum; Event; Family; Fibroblasts; G-Protein-Coupled Receptors; GTP-Binding Proteins; Golgi Apparatus; Growth; Health; Hormones; Insulin; Life; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Muscarinic Acetylcholine Receptor; Muscarinic M3 Receptor; Neoplasm Metastasis; Pancreas; Peptide Hydrolases; Physiological; Play; Process; Protein Subunits; Receptor Activation; Regulation; Role; Secretory Vesicles; Signal Transduction; Structure of beta Cell of islet; Testing; Therapeutic Intervention; Tissues; age effect; base; cytokine; design; extracellular; insulin secretion; lung Carcinoma; neoplastic cell; new therapeutic target; novel; prevent; protein complex; protein kinase D; receptor; senescence; sensor; tumor; tumor growth

DESCRIPTION (provided by applicant): We propose to examine the role of G protein coupled receptors (GPCRs) in two related physiological events - secretion and cellular senescence. The secretion of important molecules such as hormones and cytokines are regulated by GPCRs but the mechanistic basis of this regulation is not clear. We have discovered that G protein 23 complexes translocate to the Golgi on GPCR activation and induce secretory vesicle formation in the trans-Golgi. Extracellular signals can thus regulate secretion through 23 translocation. Our first aim is to test whether 23 translocation plays a role in GPCR regulation of cathepsin D secretion from a lung carcinoma cell and insulin from a pancreatic beta cell. We have found that secretion of cathepsin D, a protease that promotes tumor growth and metastasis, is regulated by a bradykinin receptor. Insulin secretion is also known to be regulated by GPCRs, including the M3 muscarinic receptor. The second aim is to examine the potential role of receptor induced G protein 23 complex translocation in cellular senescence. The third aim is to uncover mechanisms at the basis of GPCR regulation of senescence. Cellular senescence is a process by which stressed cells stop dividing but remain viable. It is thought to play contradictory roles - protecting the cell from cancerous growth but promoting proliferation of surrounding pre-neoplastic cells through enhanced secretion of various molecules. We propose to pursue these aims based on recent results that a translocation proficient G protein 3 subunit induces senescence. The role of GPCRs in cellular senescence is not clearly understood although they are the major sensors of extracellular cues. Identifying the molecular mechanisms at the basis of GPCR regulation of secretion and senescence will provide novel targets for the design of therapeutic interventions that can have an impact on cancer, diabetes and the deleterious effects of ageing.

描述（由申请人提供）：我们建议检查G蛋白偶联受体（GPCR）在两个相关的生理事件中的作用 - 分泌和细胞衰老。重要分子（例如激素和细胞因子）的分泌受GPCR的调节，但该调节的机械基础尚不清楚。我们发现G蛋白23复合物在GPCR激活中转移到高尔基体中，并在反式高尔基体中诱导分泌囊泡形成。细胞外信号因此可以通过23个易位调节分泌。我们的第一个目的是测试23个易位是否在肺癌细胞中的组织蛋白酶D分泌的GPCR调节中起作用，并从胰腺β细胞中胰岛素发挥作用。我们发现，促进肿瘤生长和转移的蛋白酶的组织蛋白酶D的分泌受Bradykinin受体调节。胰岛素分泌也受到包括M3毒蕈碱受体在内的GPCR调节。第二个目的是检查受体诱导的G蛋白23复合物在细胞衰老中的潜在作用。第三个目的是根据GPCR调节衰老。细胞衰老是一个过程，压力细胞停止分裂但保持生存。人们认为它起着矛盾的作用 - 保护细胞免受癌性的生长，但通过增强各种分子的分泌来促进周围肿瘤前细胞的增殖。我们建议基于最近的结果，即易位的G蛋白3亚基可引起衰老。尽管GPCR是细胞外提示的主要传感器，但尚未清楚地了解GPCR在细胞衰老中的作用。根据GPCR的分泌和衰老调节，确定分子机制将为设计可能影响癌症，糖尿病和衰老有害影响的治疗干预措施的设计提供新的目标。