INHIBITION OF NUCLEAR TRANSPORT BY TUMOR SUPPRESSOR CC3

肿瘤抑制剂 CC3 对核转运的抑制

• 批准号: 7460827
• 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/7460827
• 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）：该提案将探讨肿瘤细胞中核运输调节发生改变、有助于细胞凋亡抵抗和肿瘤发生的新假设。这一假设基于我们的发现，即肿瘤抑制因子 CC3/TIP30 具有作为核转运抑制剂的新细胞功能。 CC3 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。最近，发现CCS在各种肿瘤中频繁突变，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、NTF2（Ran 转运受体）和核孔蛋白相互作用。缺乏 CCS 的肿瘤细胞具有明显更高的核输入率，并且对死亡信号有抵抗力。 CCS抑制核输入的能力与其促进细胞凋亡的能力密切相关。 DNA损伤后CCS的表达以进化保守的方式被诱导，而CCS的沉默则在DNA损伤后赋予细胞凋亡抗性。高水平的 CCS 可能会抑制 DNA 损伤修复的效率。该提案的目的是了解 CC3/TIP30 在核运输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，首先有必要确定 CCS 与核运输机制组件的相互作用如何导致后者受到抑制。其次，我们将寻求证据来证明 CCS 抑制核转运在 DNA 损伤反应中发挥作用的假设，并研究 CCS 缺陷在决定 DNA 损伤后细胞命运方面的后果。第三，我们将通过探索CCS对基因组不稳定性发展的影响以及具有抑癌活性的相关蛋白的定位来阐明CCS抑癌活性的分子基础。总体而言，这些研究将描述 CCS 在正常条件下和 DNA 损伤后调节核运输中的作用。他们将确定核运输的失调如何促进肿瘤发生和细胞凋亡抵抗。检查核运输中肿瘤特异性的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目标。