INHIBITION OF NUCLEAR TRANSPORT BY TUMOR SUPPRESSOR CC3

肿瘤抑制剂 CC3 对核转运的抑制

• 批准号: 7257229
• 负责人: Emma Shtivelman
• 金额: $ 23.27万
• 依托单位: BIONOVO, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-06 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257229
• 关键词: Accounting; Affect; Apoptosis; Apoptotic; Binding; Cell Nucleus; Cell physiology; Cells; Cessation of life; Condition; DNA Damage; DNA Repair; Data; Development; Docking; Evolution; Expressed Sequence Tags; Family; Frequencies; Genomic Instability; Goals; HTATIP2 gene; Homologous Gene; Human; Importins; Karyopherins; Lead; Link; Measures; Mediating; Molecular; Movement; Mus; Mutate; Mutation; Nature; Nuclear Import; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Oncogene Proteins; Play; Process; Protein Import; Proteins; Rate; Regulation; Research Personnel; Resistance; Role; Running; Signal Transduction; Translations; Tumor Suppression; Tumor Suppressor Proteins; Tumor-Derived; Yeasts; anticancer research; base; concept; inhibitor/antagonist; mutant; neoplastic cell; novel; novel strategies; nuclear transport factor 2; nucleocytoplasmic transport; prevent; pro-apoptotic protein; receptor; repaired; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): This proposal will explore the novel hypothesis that regulation of nuclear transport is altered in tumor cells, contributing to the development of apoptotic resistance and tumorigenesis. This hypothesis is based on our findings that tumor suppressor CC3/TIP30 has a novel cellular function as an inhibitor of nuclear transport. CC3 is a pro-apoptotic protein whose expression is frequently suppressed in aggressive human tumors. Recently, it was found that CCS id frequently mutated in various tumors, though the consequences of mutations for the cellular function of CCS remains to be established. CCS interacts with karyopherins of importin D family, NTF2 (Ran transport receptor) and nucleoporins. Tumor cells lacking CCS have a measurably higher rate of nuclear import, and are resistant to death signals. The ability of CCS to inhibit nuclear import is closely linked to its ability to promote apoptosis. Expression of CCS is induced after DNA damage in an evolutionary conserved manner, while silencing of CCS confers apoptotic resistance after DNA damage. High levels of CCS might inhibit the efficiency of DNA damage repair. The goal of this proposal is to understand how the inhibitory function of CC3/TIP30 in nuclear transport accounts for its pro-apoptotic and tumor-suppressing activities. To achieve this goal, it is necessary first to determine how interactions of CCS with the components of the nuclear transport machinery lead to the inhibition of the latter. Second, we will seek proof for the hypothesis that inhibition of nuclear transport by CCS plays a role in DNA damage responses, and examine the consequences of CCS deficiency in determining cell fate after DNA damage. Third, we will elucidate the molecular basis for the tumor- suppressing activity of CCS by exploring its effect on development of genomic instability and localization of relevant proteins with tumor suppressor activities. Overall, these studies will characterize the role of CCS in regulating nuclear transport under normal conditions and after DNA damage. They will determine how deregulation of nuclear transport contributes to tumorigenesis and apoptotic resistance. Examining tumor-specific alterations in nuclear transport is a novel approach in cancer research, and CCS provides a unique target for exploring this concept.

描述（由申请人提供）：该提案将探索肿瘤细胞中核转运调节改变的新假设，有助于细胞凋亡抗性和肿瘤发生的发展。这一假设是基于我们的发现，即肿瘤抑制因子CC 3/TIP 30具有作为核转运抑制剂的新的细胞功能。CC 3是一种促凋亡蛋白，其表达在侵袭性人类肿瘤中经常受到抑制。近年来，研究发现CCS在多种肿瘤中频繁发生突变，但突变对CCS细胞功能的影响仍有待确定。CCS与输入蛋白D家族的核转运蛋白、核转运受体NTF 2和核孔蛋白相互作用。缺乏CCS的肿瘤细胞具有可测量的更高的核输入率，并且对死亡信号具有抗性。CCS抑制核输入的能力与其促进细胞凋亡的能力密切相关。CCS的表达诱导DNA损伤后，在进化上保守的方式，而沉默的CCS赋予DNA损伤后的凋亡抗性。高浓度CCS可抑制DNA损伤修复的效率。本提案的目标是了解CC 3/TIP 30在核转运中的抑制功能如何解释其促凋亡和肿瘤抑制活性。为了实现这一目标，有必要首先确定CCS与核运输机制组件的相互作用如何导致后者的抑制。第二，我们将寻求证据的假设，抑制CCS的核运输在DNA损伤反应中发挥了作用，并检查CCS缺陷的后果，在确定DNA损伤后的细胞命运。第三，我们将通过探索CCS对基因组不稳定性的发展和具有肿瘤抑制活性的相关蛋白质的定位的影响来阐明CCS肿瘤抑制活性的分子基础。总之，这些研究将描述CCS在正常条件下和DNA损伤后调节核转运的作用。他们将确定核转运的失调如何有助于肿瘤发生和凋亡抵抗。检查核转运中的肿瘤特异性改变是癌症研究中的一种新方法，CCS为探索这一概念提供了独特的靶点。