Role of Ets Genes in Transformation and Differentiation

Ets 基因在转化和分化中的作用

• 批准号: 6903300
• 负责人: Dennis K Watson
• 金额: $ 109.78万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6903300
• 关键词: breast neoplasms; clinical research; metastasis; neoplasm /cancer genetics; transcription factor

DESCRIPTION (provided by applicant): Although it is established that the Ets family of transcription factors control specific genes that contribute to normal and aberrant processes, identification of their roles in tumor metastasis remains an unresolved area requiring further investigation. Ets factors can be positive or negative regulators, and they can be intrinsic to the malignant cells or can affect stromal cells that indirectly influence cell movement. The members of this Program Project Grant will use in vitro and in vivo approaches to elucidate the upstream and downstream pathways that mediate Ets function, both in normal development and in cancer. The Program consists of three interactive Projects supported by three cores. Project 1 will test the hypothesis that the Ets factor PDEF controls multiple aspects of the multi-step metastatic process and therefore, loss of PDEF expression is a key event in the development of invasive breast cancer. Project 2 will examine a novel pathway in tumor cells that results in over-accumulation of a metastasis-inducing signaling receptor, FGF receptor; and analyze how Ets1 mediates this aberrant signaling event in promoting cell motility. Project 3 will further assess the mechanisms whereby Fli1 and Ets1 function as critical regulators of stromal homeostasis in healthy tissues, as well as their contribution to formation of reactive stroma in cancer. Specifically, Project 3 will test the hypothesis that Ets factors are integrators of the TGF-b/CTGF and Ras-MAPK signaling pathways in regulation of ECM remodeling. This in turn affects cell migration, cell survival and recruitment of perivascular cells to the newly formed vessels. Thus, the Program Project proposes experiments to elucidate the molecular pathways that underlie the roles of Ets factors in cell migration, invasion and metastasis and angiogenesis. The long-term goal of this Program is to gain new insights that will provide novel approaches for improved diagnosis and treatment of cancer.

描述（由申请人提供）：尽管已经确定Ets家族的转录因子控制有助于正常和异常过程的特异性基因，但它们在肿瘤转移中的作用的鉴定仍然是一个尚未解决的领域，需要进一步研究。Ets因子可以是正或负调节因子，并且它们可以是恶性细胞固有的，或者可以影响基质细胞，从而间接影响细胞运动。该计划项目资助的成员将使用体外和体内方法来阐明在正常发育和癌症中介导Ets功能的上游和下游途径。该计划由三个核心支持的三个互动项目组成。项目1将检验Ets因子PDEF控制多步骤转移过程的多个方面的假设，因此，PDEF表达的丧失是浸润性乳腺癌发展中的关键事件。项目2将研究肿瘤细胞中导致转移诱导信号受体FGF受体过度积累的新途径;并分析Ets 1如何介导这种异常信号事件促进细胞运动。项目3将进一步评估Fli 1和Ets 1作为健康组织中基质稳态的关键调节因子的机制，以及它们对癌症反应性基质形成的贡献。具体而言，项目3将检验Ets因子是调节ECM重塑的TGF-β/CTGF和Ras-MAPK信号通路的整合剂的假设。这反过来又影响细胞迁移、细胞存活和血管周围细胞向新形成的血管的募集。因此，该计划项目提出实验来阐明Ets因子在细胞迁移、侵袭和转移以及血管生成中的作用的分子途径。该计划的长期目标是获得新的见解，为改善癌症的诊断和治疗提供新的方法。