Role and Regulaton of the Human DEK Proto-Oncogene

人类DEK原癌基因的作用和调控

• 批准号: 8540348
• 负责人: Susanne I Wells
• 金额: $ 25.07万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8540348
• 关键词: Acute; Advanced Malignant Neoplasm; Affect; Atlas of Cancer Mortality in the United States; Benign; Binding; Biological Assay; Biological Models; Cancer Patient; Cause of Death; Cell Proliferation; Cell Survival; Cell model; Cells; Cessation of life; Chemosensitization; Chromatin; DEK gene; Data; Development; Diagnosis; Diagnostic; Diagnostic Neoplasm Staging; Disease; Epithelial; Epithelium; Funding; Future; Growth; HPV E7; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Human body; Human papillomavirus 16; Hyperplasia; Immunodeficient Mouse; Knockout Mice; Left; Ligands; Link; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Maps; Mass Spectrum Analysis; Mediating; Mesenchymal; Messenger RNA; Modeling; Molecular; Mus; Mutagens; Normal Cell; Nuclear; Oncogenes; Oncogenic; Outcome; Pathway interactions; Phenotype; Play; Pre-Clinical Model; Preparation; Production; Proteins; Proto-Oncogenes; Publishing; Regulation; Reporting; Research Project Grants; Resistance; Retinoblastoma; Role; Signal Pathway; Signal Transduction; Skin Papilloma; Squamous Epithelium; Squamous cell carcinoma; Structure; Tertiary Protein Structure; Testing; Therapeutic; Transgenic Mice; Tumor Pathology; Tumor Suppressor Proteins; Up-Regulation; Validation; Work; Xenograft procedure; base; cancer cell; cancer stem cell; cancer type; carcinogenesis; cell growth; cell type; chemotherapy; combat; gain of function; high risk; human Dek protein; human NUP214 protein; improved; in vivo; keratin 5; keratinocyte; leukemia; mouse model; mutant; neoplastic cell; novel strategies; overexpression; promoter; research study; retinoblastoma tumor suppressor; self-renewal; stem cell population; therapeutic target; time use; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): The proposed work builds on the previously funded research project entitled "Role and regulation of the human DEK oncogene." The original application was focused on the role of DEK in HPV positive cervical cancer cells, based on the observation that DEK was up-regulated by the high risk HPV E7 oncogene. We and others subsequently demonstrated that DEK is controlled by E2F/Rb pathways and thus also widely over-expressed in HPV negative cancers. DEK had been suspected to carry oncogenic activities since the early 1990s. In the past several years, we were able to prove such activities for the first time using organotypic epithelial raft cultures and classical keratinocyte transformation assays. Furthermore, we reported a new DEK knockout mouse model which was partially resistant to the development of chemically induced skin papillomas. Herein we propose to investigate the molecular role of DEK in head and neck squamous cell carcinoma (HNSCCs), which can be positive or negative for HPV in cancer patients. In Aim 1, we will carry out DEK loss and gain of function studies in mice to determine the requirement and sufficiency for HNSCC development. In Aim 2, we will investigate newly identified DEK activities in the regulation of b-catenin signaling, EMT, cellular invasion and self-renewal. These experiments will be performed in primary human HNSCC cells. In Aim 3, we will carry out structure-function studies to map tumor-associated DEK domains and to identify nuclear DEK-interacting factors. The results will provide an important first step in advancing our understanding of molecular networks by which this versatile chromatin topology regulator activates oncogenic signaling and phenotypes in human cells (Aim 2) and HNSCC development in mice (Aim 1).

描述（由申请人提供）：拟议的工作建立在以前资助的研究项目，题为“作用和调节的人类DEK癌基因。“最初的应用集中在DEK在HPV阳性宫颈癌细胞中的作用，基于DEK被高危HPV E7癌基因上调的观察。我们和其他人随后证明DEK受E2 F/Rb通路控制，因此在HPV阴性癌症中也广泛过表达。自20世纪90年代初以来，DEK一直被怀疑携带致癌活性。在过去的几年里，我们首次使用器官型上皮筏培养物和经典的角质形成细胞转化测定来证明此类活性。此外，我们报道了一种新的DEK基因敲除小鼠模型，该模型对化学诱导的皮肤乳头状瘤的发展具有部分抗性。在此，我们建议研究DEK在头颈部鳞状细胞癌（HNSCCs）中的分子作用，这些癌患者的HPV阳性或阴性。在目标1中，我们将在小鼠中进行DEK功能丧失和获得研究，以确定HNSCC发展的需求和充分性。在目标2中，我们将研究新发现的DEK活动在调节β-连环蛋白信号传导，EMT，细胞侵袭和自我更新。这些实验将在原代人HNSCC细胞中进行。在目标3中，我们将进行结构-功能研究，以绘制肿瘤相关的DEK结构域，并确定核DEK相互作用因子。这些结果将为推进我们对分子网络的理解提供重要的第一步，通过该分子网络，这种多功能染色质拓扑结构调节剂激活人类细胞中的致癌信号传导和表型（Aim 2）以及小鼠中的HNSCC发展（Aim 1）。