The Role of EphA2 in UV-mediated Apoptosis

描述(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压力，细胞进化出一个复杂的信号分子网络来检测这些扰动并招募一系列反应来对抗侮辱。这些传入信号汇聚在一系列转录因子上，这些转录因子协调调节基因的表达，这些基因让细胞暂停以纠正细胞损伤或执行凋亡程序。可以说，对陆地生物来说，最普遍的环境应激源是紫外线辐射(UVR)，而这种广泛暴露在人类身上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它是否有能力应对早期UVR威胁的生理挑战。为了更好地了解这些早期事件，我们最近开始在原代色素细胞中鉴定UVR诱导的基因。在初步研究中，我们发现受体酪氨酸激酶EphA2在黑素细胞和其他类型的细胞中被紫外线辐射上调，并被一种常见的黑色素瘤癌基因激活的NRAS上调。最值得注意的是，EphA2似乎是对UVR--这些细胞最常见的外源性应激源--做出反应时，细胞凋亡的重要中介。在这项应用中，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UVR应激诱导基因在完整皮肤中的位置。在最后一个目标中，我们将在一种新的黑色素瘤光癌小鼠模型中研究紫外线应激与肿瘤发生之间的联系。 项目叙事。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后果。在初步研究中，我们发现了一种UVR应激诱导基因EphA2，它在UVR诱导的细胞凋亡中扮演着重要的中介角色。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，直到今天，这种黑色素瘤仍然无法治愈。

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.