The Role of EphA2 in UV-mediated Apoptosis

EphA2 在紫外线介导的细胞凋亡中的作用

• 批准号: 7532074
• 负责人: HENSIN TSAO
• 金额: $ 26.36万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532074
• 关键词: Alleles; Apoptosis; Apoptotic; Cell physiology; Cells; Cessation of life; Complex; Development; EPHA2 gene; Event; Functional disorder; Gene Expression; Genes; Goals; Human; In Vitro; Knockout Mice; Laboratories; Link; Malignant Neoplasms; Mediating; Mediation; Mediator of activation protein; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular; Mus; Mutagenesis; N-ras Genes; NRAS gene; Oncogenes; Oncogenic; Organism; Pathway interactions; Physiological; Pigments; Positioning Attribute; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Role; Signal Transduction; Signaling Molecule; Skin; Skin Cancer; Source; Stress; Therapeutic; Tumor Suppressor Genes; Ultraviolet Rays; biological adaptation to stress; cell injury; cell type; day; in vivo; melanocyte; melanoma; novel; p21 N-Ras Protein; programs; research study; response; stressor; success; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): In order to contend with ongoing physiological stress imposed by the local microenvironment or by endogenous oxidative processes, cells have evolved a complex network of signaling molecules to detect these perturbations and to recruit an ensemble of responses to countermand the insult. These afferent signals converge on a host of transcription factors that coordinately regulate the expression of genes which give cells pause to rectify the cellular injury or to execute an apoptotic program. Arguably, the most ubiquitous source of environmental stress for terrestrial organisms is ultraviolet radiation (UVR) and the most lethal consequence of this widespread exposure in human is malignant melanoma. The success of the aspiring melanoma cell is critically dependent on its ability to negotiate the physiological challenges of early UVR threat. In order to better understand these early events, we recently set out to identify UVR-inducible genes in primary pigment cells. In preliminary studies, we discovered that the receptor tyrosine kinase, EPHA2, is upregulated by UVR in melanocytes and other cells types and by a common melanoma oncogene, activated NRAS. Most notably, EphA2 appears to be an essential mediator of apoptosis in response to UVR - the most common exogenous stressor for these cells. In this application, our overarching goal is to understand the role of EphA2 in regulating the UVR stress response and potential downstream tumorigenesis. In the first two Aims, we will explore the mechanism by which EphA2 induces apoptosis and expand on its position as a UVR stress-inducible gene in intact skin. In the last Aim, we will investigate the link between UVR stress and oncogenesis in a novel murine model of melanoma photocarcinogenesis. PROJECT NARRATIVE. Malignant melanoma is possibly the most lethal consequence of long-term ultraviolet radiation (UVR) stress and mutagenesis. In preliminary studies, we identified a UVR stress-inducible gene, EPHA2, which empirically behaves as an essential mediator of UVR-induced apoptosis. As this gene has been implicated in the pathophysiology of multiple cancers, we propose to elucidate the mechanism by which EPHA2 modulates cellular death or survival. These clues will undoubtedly drive therapeutic developments in metastatic melanoma, which, to this day, remains incurable.

描述（由申请人提供）：为了应对由局部微环境或内源性氧化过程施加的持续生理应激，细胞已经进化出复杂的信号分子网络来检测这些扰动并招募一组反应来对抗侮辱。这些传入信号汇聚在许多转录因子上，这些转录因子协调调节基因的表达，使细胞暂停以纠正细胞损伤或执行凋亡程序。可以说，陆地生物最普遍的环境压力来源是紫外线辐射（UVR），而这种广泛暴露在人类中最致命的后果是恶性黑色素瘤。有抱负的黑色素瘤细胞的成功关键取决于其应对早期紫外线威胁的生理挑战的能力。为了更好地了解这些早期事件，我们最近着手鉴定初级色素细胞中的紫外线诱导基因。在初步研究中，我们发现黑色素细胞和其他细胞类型中的 UVR 以及常见的黑色素瘤癌基因（激活的 NRAS）可上调受体酪氨酸激酶 EPHA2。最值得注意的是，EphA2 似乎是响应 UVR 的细胞凋亡的重要介质，UVR 是这些细胞最常见的外源应激源。在此应用中，我们的首要目标是了解 EphA2 在调节 UVR 应激反应和潜在的下游肿瘤发生中的作用。在前两个目标中，我们将探索 EphA2 诱导细胞凋亡的机制，并扩展其作为完整皮肤中 UVR 应激诱导基因的地位。在最后一个目标中，我们将在黑色素瘤光致癌的新型小鼠模型中研究紫外线应激与肿瘤发生之间的联系。 项目叙述。恶性黑色素瘤可能是长期紫外线辐射 (UVR) 应激和诱变最致命的后果。在初步研究中，我们鉴定了一个 UVR 应激诱导基因 EPHA2，根据经验，该基因是 UVR 诱导细胞凋亡的重要介质。由于该基因与多种癌症的病理生理学有关，我们建议阐明 EPHA2 调节细胞死亡或存活的机制。这些线索无疑将推动转移性黑色素瘤的治疗发展，迄今为止，转移性黑色素瘤仍然无法治愈。