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：癌细胞的添加机制在驱动创世记中的重点是giren theren there therby。当活性作为转录因子和损伤反应蛋白的情况下，我们发现ATF ATF的构成定位会损害蛋白质中新鉴定的蛋白质中的蛋白质。对于Mi Toodrial外膜（MOM），它会损害MOM的潜力并增强凋亡。此外，它会减弱或丢失，ATF2对妈妈的能力由PKC Epsilon控制（PKC？）。，有效地将ATF2锁定在细胞核中并预防米奇德里亚（Mitchondria）的功能。对ATF2新型癌变的控制，Ando为研究黑色素瘤发展和进步的未识别途径提供了独特的机会。，使用细胞生物学和新的遗传小鼠小鼠模型。黑色素瘤的上调，ATF2抑制剂的重要性和肿瘤的ATF2作用中的机制。促进黑色素瘤细胞中ATF2核输出ATF2的化合物对黑色素瘤的治疗方式。