The role of the Ras effector Nore1a in tumor suppression

Ras效应子Nore1a在肿瘤抑制中的作用

• 批准号: 7986980
• 负责人: Geoffrey J. Clark
• 金额: $ 27.83万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986980
• 关键词: Animal Model; Apoptosis; Apoptotic; Binding; Cell Cycle Arrest; Complex; Defect; Development; Diagnostic; Epigenetic Process; Family; Human; Knockout Mice; Link; Malignant Neoplasms; Mediating; Oncogene Proteins; Oncogenic; Pathway interactions; Phenotype; Physiological; Play; Prognostic Marker; Protein Kinase; Protein p53; Proteins; Renal Cell Carcinoma; Role; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Syndrome; TP53 gene; Tumor Suppression; Tumor Suppressor Proteins; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein; design; homeodomain; in vivo; loss of function; member; mouse model; neoplastic cell; novel; novel diagnostics; public health relevance; research study; restoration; senescence; small hairpin RNA; therapeutic target; tumor; tumorigenic

DESCRIPTION (provided by applicant): Nore1a is a member of the RASSF family of tumor suppressors. It is frequently down- regulated in primary human tumors and is genetically linked to a familial human cancer syndrome. Over-expression of Nore1a can promote apoptosis, cell cycle arrest and senescence. Restoration of Nore1a expression to physiological levels blocks the tumorigenic phenotype and shRNA mediated inactivation of Nore1a enhances the transformed phenotype. Thus, the evidence that Nore1a is an important human tumor suppressor is strong. Nore1a also directly binds the Ras oncoprotein and appears to serve as a novel effector, mediating some of the pro-apoptotic and pro-senescent effects of oncogenic Ras. Thus, loss of function of Nore1a may be particularly important to Ras dependent tumors, allowing oncogenic Ras to circumvent its apoptotic and senescent functions. However, the signaling pathways controlled by Nore1a have not been defined, and no animal model for Nore1a function has been investigated. Furthermore, the effects of loss of Nore1a function on the transforming effects of oncogenic Ras have not been characterized. Nore1a lacks obvious enzymatic activity, and little is known about its mechanism of action. However, it has been hypothesized that it may serve as a scaffolding protein to modulate the formation of tumor suppressor complexes. We have now identified two tumor suppressors in endogenous complex with Nore1a: the Homeodomain Interacting Protein Kinase 2 (HIPK2) protein and the Von Hippel-Lindau protein (VHL), a notorious tumor suppressor which plays a critical role in the development of the majority of Renal Cell Carcinomas (RCC). Both HIPK2 and VHL act, in part, by directly modulating the master tumor suppressor p53. Defects in p53 have been detected in approximately 50% of human tumors, and it may be argued that p53 is the most critical tumor suppressor yet identified. Thus, Nore1a may function by modulating p53 by dual pathways and could serve as part of the well known, but poorly characterized, link between Ras and p53. We propose a series of experimental aims designed to determine the precise role of Nore1a loss of function in the development of the tumorigenic phenotype and in Ras mediated transformation. This includes a proposal to determine the role of the Nore1a/Ras interaction in vivo, using a novel Nore1a knockout mouse model. We will then determine if the mechanism of action of Nore1a involves the modulation of the HIPK2 or VHL tumor suppressors, and whether Nore1a acts to integrate their effects upon p53. We anticipate that these experiments will identify Nore1a as an important novel diagnostic and therapeutic target for cancer. PUBLIC HEALTH RELEVANCE: These studies will serve to define the role of a novel potential tumor suppressor, Nore1a, in human cancer. They will determine if Nore1a is an important diagnostic/prognostic marker for cancer. They will also determine if Nore1a may be a suitable candidate for the development of epigenetic therapy to restore its normal function in tumor cells.

描述（由申请人提供）：Nore1a是RASSF肿瘤抑制剂家族的成员。它经常在原发性人类肿瘤中受到调节，并在遗传上与家族性人类癌症综合征有关。 Nore1a的过表达可以促进凋亡，细胞周期停滞和衰老。 Nore1a表达对生理水平的恢复阻碍了致瘤的表型，而shRNA介导的Nore1a失活则增强了转化的表型。因此，Nore1a是重要的人类肿瘤抑制剂的证据很强。 Nore1a还直接结合了Ras癌蛋白，并且似乎是一种新型效应子，介导了致癌Ras的一些促凋亡和促介质作用。因此，Nore1a功能的丧失对于RAS依赖性肿瘤可能尤其重要，从而使致癌性RAS可以规避其凋亡和衰老功能。但是，尚未定义由Nore1a控制的信号通路，并且尚未研究Nore1a功能的动物模型。此外，尚未表征Nore1a功能丧失对致癌Ras转化作用的影响。 Nore1a缺乏明显的酶活性，并且对其作用机理知之甚少。但是，已经假设它可以用作脚手架蛋白来调节肿瘤抑制复合物的形成。现在，我们已经确定了Nore1a内源性复合物中的两个肿瘤抑制剂：同源域相互作用的蛋白激酶2（HIPK2）蛋白和Von Hippel-Lindau蛋白（VHL），这是一种臭名昭著的肿瘤抑制，这在肾脏细胞电脑瘤（RCC）的主要角色中起着至关重要的作用。 HIPK2和VHL都通过直接调节主肿瘤抑制p53的作用。在大约50％的人类肿瘤中已经检测到p53中的缺陷，可以说p53是尚未发现的最关键的肿瘤抑制剂。因此，Nore1a可能通过双重途径调节p53来起作用，并且可以作为RAS和p53之间的众所周知但表征较差的一部分。 我们提出了一系列实验目的，旨在确定Nore1a功能丧失在肿瘤表型发展和RAS介导的转化中的精确作用。这包括使用新型的Nore1a基因敲除小鼠模型来确定体内Nore1a/Ras相互作用的作用的建议。然后，我们将确定Nore1a的作用机理是否涉及HIPK2或VHL肿瘤抑制剂的调节，以及Nore1a是否作用于整合其对p53的影响。我们预计这些实验将识别出Nore1a是癌症的重要诊断和治疗靶标。 公共卫生相关性：这些研究将有助于定义一种新型潜在的抑制肿瘤Nore1a在人类癌症中的作用。他们将确定Nore1a是否是癌症的重要诊断/预后标记。他们还将确定Nore1a是否可能是发展表观遗传疗法以恢复其在肿瘤细胞中正常功能的合适候选者。