Rap 1-Mediated Protein Transport in Oral Cancer

Rap 1 介导的口腔癌蛋白质转运

• 批准号: 6960181
• 负责人: Nisha J D'Silva
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6960181
• 关键词: athymic mouse; cell growth regulation; cell line; cell proliferation; guanine nucleotide binding protein; keratinocyte; molecular oncology; nuclear transport; oral pharyngeal neoplasm; protein isoforms; protein localization; protein protein interaction; protein transport; squamous cell carcinoma

DESCRIPTION (provided by applicant): The aggressive surgical and radiologic treatment for oral cancer is physically and emotionally debilitating and has not improved prognosis (<50% 5 year survival) in the past four decades. Since cancer is the endpoint of uncontrolled cell proliferation, elucidation of the signaling cascade controlling cell proliferation in normal and malignant oral keratinocytes is critical to the identification of specific treatment targets. In oral cancer these signaling mechanisms are relatively uncharacterized but an exciting and significant area of research is the signaling cascade triggered by rap1A and rap1B, ras-like proteins that have been shown to have oncogenic and/or tumor suppressive properties in mesenchymal cells. In previous studies we found that inactivation of rap1 by rap1GAP, stimulated proliferation in non-malignant keratinocytes but inhibited proliferation in oral cancer. Rap1GAP inactivates rap1A and rap1B, the 95% identical isoforms, both of which are expressed in normal and malignant keratinocytes. Although rap1A and rap1B have been linked to growth in several cells, the interaction between these proteins in the same cell has not been explored. Furthermore, our laboratory recently discovered that rap1 is strongly expressed in the nucleus of malignant keratinocytes and that growth factors in serum induce nuclear translocation. Hence, it is likely that rap1A and rap1B interact with transport and effector proteins to regulate proliferation. The central hypothesis is that in oral cancer there is a disruption in rap1-mediated nuclear transport with enhanced nuclear translocation of pro-proliferative proteins. The objectives of this proposal are to investigate the interaction between rap1A and rap1B in regulating proliferation in normal and malignant keratinocytes; and to identify the proteins that are transported by rap1A and rap1B to the nucleus to regulate proliferation. The significance of this research is that it explores an important and novel mechanism for nucleocytoplasmic transport of pro-proliferative proteins in oral cancer, thereby identifying novel treatment targets.

描述（由申请人提供）：口腔癌的积极手术和放射治疗使身体和情感衰弱，并且在过去四十年中没有改善预后（<50%的5年生存率）。由于癌症是不受控制的细胞增殖的终点，因此阐明正常和恶性口腔角质形成细胞中控制细胞增殖的信号级联对于鉴定特异性治疗靶点至关重要。在口腔癌中，这些信号传导机制相对未被表征，但一个令人兴奋和重要的研究领域是由rap 1A和rap 1B触发的信号级联，ras样蛋白已被证明在间充质细胞中具有致癌和/或肿瘤抑制特性。在以前的研究中，我们发现rap 1GAP对rap 1的失活刺激了非恶性角质形成细胞的增殖，但抑制了口腔癌细胞的增殖。Rap 1GAP使rap 1A和rap 1B失活，rap 1A和rap 1B是95%相同的同种型，两者都在正常和恶性角质形成细胞中表达。尽管rap 1A和rap 1B与几种细胞的生长有关，但尚未探索同一细胞中这些蛋白质之间的相互作用。此外，本实验室最近发现rap 1在恶性角质形成细胞的细胞核中强烈表达，并且血清中的生长因子可诱导细胞核转位。因此，rap 1A和rap 1B可能与转运蛋白和效应蛋白相互作用以调节增殖。核心假设是，在口腔癌中，rap 1介导的核转运中断，促增殖蛋白的核转位增强。本提案的目的是研究rap 1A和rap 1B之间的相互作用，在正常和恶性角质形成细胞的增殖调节，并确定由rap 1A和rap 1B运送到细胞核，以调节增殖的蛋白质。这项研究的意义在于它探索了口腔癌中促增殖蛋白的核质转运的重要和新机制，从而确定了新的治疗靶点。