INHIBITION OF NUCLEAR TRANSPORT BY TUMOR SUPPRESSOR CC3

描述（由申请人提供）：本提案将探讨肿瘤细胞中核转运调节的改变，促进凋亡抵抗和肿瘤发生的新假设。这一假设是基于我们发现肿瘤抑制因子CC3/TIP30作为核转运抑制剂具有新的细胞功能。CC3是一种促凋亡蛋白，其表达在侵袭性人类肿瘤中经常被抑制。最近，人们发现CCS在各种肿瘤中经常发生突变，尽管突变对CCS细胞功能的影响仍有待确定。CCS与输入D家族的核细胞蛋白、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。在DNA损伤后，CCS以进化保守的方式被诱导表达，而在DNA损伤后，CCS沉默会产生凋亡抗性。高水平的CCS可能会抑制DNA损伤修复的效率。本提案的目的是了解CC3/TIP30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，首先有必要确定CCS与核转运机制组成部分的相互作用如何导致后者的抑制。其次，我们将为CCS抑制核转运在DNA损伤反应中发挥作用的假设寻找证据，并研究CCS缺乏在DNA损伤后决定细胞命运的后果。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瘤活性的相关蛋白的定位来阐明其抑瘤活性的分子基础。总的来说，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。他们将确定解除核转运如何促进肿瘤发生和细胞凋亡抵抗。研究核转运中的肿瘤特异性改变是癌症研究中的一种新方法，而CCS为探索这一概念提供了一个独特的目标。

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.