ATF2 Oncogenic Addiction in Melanoma

ATF2 黑色素瘤致癌成瘾

基本信息

批准号：
8579169
负责人：
Ze'ev A Ronai
金额：
$ 40.46万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8579169
关键词：
ATR protein kinase Activating Transcription Factor 2 Address Animals Apoptosis Attenuated Automobile Driving Biogenesis Biological Biological Assay CREB1 gene Cell Culture Techniques Cell Cycle Regulation Cell Death Cell Nucleus Cells Cellular biology Clinical Collection Cytosol DNA Damage Development Family Genetic Genotoxic Stress Heterodimerization Image JUN gene Knock-in Mouse Mediating Melanoma Cell Membrane Potentials Methods Mitochondria Modality Modeling Mus NRAS gene Nuclear Nuclear Export Oncogenes Oncogenic Outer Mitochondrial Membrane Pathway interactions Play Process Proteins Protocols documentation Research Design Role Series Signal Transduction Skin Carcinogenesis Skin Papilloma Staging Testing Therapeutic Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation addiction bZIP Domain base cell type innovation keratinocyte melanocyte melanoma member mouse model mutant novel novel therapeutics oncogene addiction prevent protein function protein kinase C epsilon public health relevance response small molecule transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Understanding the mechanism underlying oncogene addiction is of major importance given their role in driving tumorigenesis. This proposal focuses on a new discovery, whereby we reveal a novel mechanism for oncogene addiction. A genetic N-RAS/Ink4a mouse melanoma model established the oncogenic role of the transcription factor ATF2 in melanoma. This is achieved through its constitutive nuclear localization, where ATF2 is active as a transcription factor and DNA damage response protein. We recently discovered that constitutive nuclear localization of ATF2 impairs a newly identified function for this protein in te cytosol. Following exposure of cells to genotoxic, ATF2 is exported from the nucleus to enable its localization at the mitochondrial outer membrane (MOM), where it impairs MOM potential and augments apoptosis. This process underlies a newly disclosed mechanism by which ATF2 contributes to cell death. Although this mitochondrial function of ATF2 is seen in most cell types, it is attenuated or lost in melanoma. Moreover, the ability of ATF2 to localize to the MOM is controlled by PKC epsilon (PKC¿). Melanoma cells express high levels of PKC¿, which effectively locks ATF2 in the nucleus and prevents its export and function at the mitochondria. These observations form the basis for our hypothesis that PKC¿ control of ATF2 nuclear export constitutes a novel paradigm for oncogene addiction in melanoma, and therefore offers unique opportunities for studying unrecognized pathways underlying melanoma development & progression, which can be exploited for development of innovative therapeutic modalities. Our proposed studies are designed to answer key questions that emerge from our recent discovery of ATF2 addiction to PKC¿, using cell biology, and new relevant genetic mouse melanoma models. Among the cardinal questions we will address are: what underlies PKC¿ upregulation in melanoma, the significance of ATF2's tumor suppressor activities and the mechanisms underlying oncogenic ATF2 activity. We will establish conditional ATF2 knock-in mice, which will allow us to define oncogenic and tumor suppressor functions of ATF2, respectively. Lastly, we will use a high- content screen, already established, to identify natural compounds that promote nuclear export of ATF2 in melanoma cells, thereby offering a novel therapeutic modality for melanoma.

描述（通过应用程序提供）：了解癌基因成瘾的机制至关重要，鉴于它们在驱动肿瘤发生中的作用。该提案的重点是新发现，我们揭示了一种新颖的癌基因成瘾机制。遗传N-RAS/INK4A小鼠黑色素瘤模型建立了转录因子ATF2在黑色素瘤中的致癌作用。这是通过其组成核定位来实现的，其中ATF2作为转录因子和DNA损伤反应蛋白活跃。我们最近发现，ATF2的本构核定位会损害该蛋白在TE细胞质中的新功能。细胞暴露于遗传毒性后，将ATF2从细胞核中导出，以使其在线粒体外膜（MOM）中的定位，在此损害了MOM的潜力并增加了凋亡。该过程是新披露的机制的基础，ATF2促进了细胞死亡。尽管在大多数细胞类型中都可以看到ATF2的这种线粒体功能它在黑色素瘤中被减弱或丢失。此外，pkc epsilon（PKC¿）控制了ATF2本地化与MOM的能力。黑色素瘤细胞表达了高水平的PKC？，该细胞有效地将ATF2锁定在细胞核中，并防止其在线粒体上的出口和功能。这些观察结果构成了我们假设的基础：pkc。对ATF2核出口的控制构成了黑色素瘤中癌基因成瘾的新型范式，因此为研究黑色素瘤发育和进展的未识别途径提供了独特的机会，可以探索用于创新治疗模态的发展。我们提出的研究旨在回答我们最近发现ATF2成瘾对PKC¿的关键问题，使用细胞生物学和新的相关遗传小鼠黑色素瘤模型。我们将要解决的主要问题中是：黑色素瘤中PKC的上调是什么，ATF2肿瘤抑制活性的重要性以及致癌性ATF2活性的机制。我们将建立条件ATF2敲击小鼠，这将使我们能够分别定义ATF2的致癌和肿瘤抑制功能。最后，我们将使用已经建立的高含量筛选来识别促进黑色素瘤细胞中ATF2核输出的天然化合物，从而为黑色素瘤提供一种新型的疗法方式。