Role and Regulaton of the Human DEK Proto-Oncogene

人类DEK原癌基因的作用和调控

基本信息

  • 批准号:
    8387662
  • 负责人:
  • 金额:
    $ 26.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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). PUBLIC HEALTH RELEVANCE: DEK upregulation has been clinically noted for many human tumor types, and DEK has thus been widely referred to as an oncogene. We have published that DEK supports the initial stages of cancer development, and generated the first preclinical model systems in which therapeutic DEK targeting approaches can now be tested. These models include organotypic epithelial rafts, human xenografts and DEK knockout mice. DEK inhibition selectively targeted epithelial tumor cells: acute DEK depletion caused the death and chemosensitization of cancer cells. However, DEK depletion did not affect normal cells to the same extent, and left differentiated cells which comprise the majority of human epithelium unaffected. HNC is a devastating disease with poor survival, and new approaches to diagnose and treat this disease are urgently needed. Preliminary data herein support critical roles for DEK in HNC growth, and also invasion and thus cancer cell dissemination. Thus DEK might be targeted in advanced cancers which are responsible for the great majority of HNC-related deaths. The application determines the role of DEK in the activation of b-catenin signaling pathways which we believe are a major contributor to HNC growth and spread in the human body. We anticipate that the results of the proposed studies in HNC will have broad implications for all cancers in which DEK is overexpressed. Based upon our preliminary and published findings, we postulate that DEK will be a useful diagnostic marker, and that its targeting - perhaps in conjunction with conventional chemotherapies - will improve therapeutic outcomes at both early and late cancer stages.
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。在过去的几年中,我们能够证明这样的活动,第一次使用器官型上皮筏文化和经典的角质形成细胞转化测定。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)。 公共卫生关系:临床上已经注意到许多人类肿瘤类型的DEK上调,因此DEK被广泛称为癌基因。我们已经发表了DEK支持癌症发展的初始阶段,并生成了第一个临床前模型系统,其中可以测试治疗性DEK靶向方法。这些模型包括器官型上皮筏、人异种移植物和DEK敲除小鼠。DEK抑制选择性靶向上皮肿瘤细胞:急性DEK耗竭导致癌细胞死亡和化疗增敏。然而,DEK耗竭对正常细胞没有相同程度的影响,并且使构成大部分人类上皮的分化细胞不受影响。HNC是一种生存率低的毁灭性疾病,迫切需要诊断和治疗这种疾病的新方法。本文的初步数据支持DEK在HNC生长中的关键作用,以及侵袭和因此的癌细胞传播。因此,DEK可能是晚期癌症的靶点,而晚期癌症是大多数HNC相关死亡的原因。该应用确定了DEK在激活β-连环蛋白信号通路中的作用,我们认为β-连环蛋白信号通路是HNC在人体内生长和扩散的主要贡献者。我们预计,HNC中拟议研究的结果将对DEK过表达的所有癌症产生广泛影响。基于我们的初步和已发表的研究结果,我们假设DEK将是一个有用的诊断标志物,其靶向-可能与常规化疗结合-将改善早期和晚期癌症的治疗结果。

项目成果

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Susanne I Wells其他文献

Susanne I Wells的其他文献

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{{ truncateString('Susanne I Wells', 18)}}的其他基金

New activities of the human DEK oncogene
人类DEK癌基因的新活性
  • 批准号:
    10523123
  • 财政年份:
    2019
  • 资助金额:
    $ 26.67万
  • 项目类别:
New activities of the human DEK oncogene
人类DEK癌基因的新活性
  • 批准号:
    9914529
  • 财政年份:
    2019
  • 资助金额:
    $ 26.67万
  • 项目类别:
New activities of the human DEK oncogene
人类DEK癌基因的新活性
  • 批准号:
    10304189
  • 财政年份:
    2019
  • 资助金额:
    $ 26.67万
  • 项目类别:
New activities of the human DEK oncogene
人类DEK癌基因的新活性
  • 批准号:
    10062494
  • 财政年份:
    2019
  • 资助金额:
    $ 26.67万
  • 项目类别:
Strengthening epidermal defenses for the prevention of HPV infection and replication
加强表皮防御,预防 HPV 感染和复制
  • 批准号:
    10524745
  • 财政年份:
    2018
  • 资助金额:
    $ 26.67万
  • 项目类别:
Strengthening epidermal defenses for the prevention of HPV infection and replication
加强表皮防御,预防 HPV 感染和复制
  • 批准号:
    10304915
  • 财政年份:
    2018
  • 资助金额:
    $ 26.67万
  • 项目类别:
FA pathway activities in the normal and transformed epidermis
正常和转化表皮中的 FA 途径活性
  • 批准号:
    10216196
  • 财政年份:
    2018
  • 资助金额:
    $ 26.67万
  • 项目类别:
FA pathway activities in the normal and transformed epidermis
正常和转化表皮中的 FA 途径活性
  • 批准号:
    10454251
  • 财政年份:
    2018
  • 资助金额:
    $ 26.67万
  • 项目类别:
Strengthening epidermal defenses for the prevention of HPV infection and replication
加强表皮防御,预防 HPV 感染和复制
  • 批准号:
    10053333
  • 财政年份:
    2018
  • 资助金额:
    $ 26.67万
  • 项目类别:
FA pathway activities in the normal and transformed epidermis
正常和转化表皮中的 FA 途径活性
  • 批准号:
    9767108
  • 财政年份:
    2018
  • 资助金额:
    $ 26.67万
  • 项目类别:
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