The Role of EphA2 in UV-mediated Apoptosis

EphA2 在紫外线介导的细胞凋亡中的作用

基本信息

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
项目类别：
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

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

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项目摘要

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）：为了与局部微环境或内源性氧化过程施加的持续的生理压力抗衡，细胞已经进化了一个复杂的信号分子网络，以检测这些扰动并募集了对互换和互换的反应的整体。这些传入信号汇聚在许多转录因子上，这些转录因子协同调节基因的表达，这些基因表达会使细胞停顿以纠正细胞损伤或执行凋亡程序。可以说，陆地生物的环境压力最普遍的来源是紫外线辐射（UVR），这种广泛暴露在人类中的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取决于其谈判早期UVR威胁的生理挑战的能力。为了更好地理解这些早期事件，我们最近着手鉴定原代色素细胞中的UVR诱导基因。在初步研究中，我们发现，在黑色素细胞和其他细胞类型中，UVR以及癌基因的常见黑色素瘤在激活的NRA中被UVR上调。最值得注意的是，Epha2似乎是响应UVR的凋亡的必不可少的介体，UVR是这些细胞最常见的外源性应激源。在此应用中，我们的总体目标是了解Epha2在调节UVR应激反应和潜在下游肿瘤发生中的作用。在前两个目标中，我们将探讨EPHA2诱导凋亡并扩大其作为完整皮肤中UVR应激诱导基因的位置的机制。在最后一个目的中，我们将在新型的黑色素瘤光钙化发生鼠模型中研究UVR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）应激和诱变的最致命的后果。在初步研究中，我们鉴定了一个UVR应激诱导的基因Epha2，从经验上看是UVR诱导的细胞凋亡的必不可少的介体。由于该基因与多种癌症的病理生理学有关，因此我们建议阐明Epha2调节细胞死亡或存活的机制。这些线索无疑会推动转移性黑色素瘤的治疗发展，直到今天，这些发展仍然无法治愈。