INHIBITION OF NUCLEAR TRANSPORT BY TUMOR SUPPRESSOR CC3

描述(申请人提供)：这项提案将探索新的假设，即在肿瘤细胞中核运输的调节被改变，有助于细胞凋亡抵抗和肿瘤发生的发展。这一假说是基于我们的发现，即肿瘤抑制基因CC3/TIP30具有作为核运输抑制因子的新的细胞功能。CC3是一种促凋亡蛋白，在人类侵袭性肿瘤中的表达经常被抑制。最近，人们发现CCS id在各种肿瘤中经常发生突变，但突变对CCS细胞功能的影响尚不清楚。CCS与Importin D家族的核粘附素、NTF2(RAN转运蛋白受体)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抵抗力。CCS抑制核进口的能力与其促进细胞凋亡的能力密切相关。CCS的表达是在DNA损伤后以进化保守的方式诱导的，而沉默CCS则在DNA损伤后提供了抗凋亡的能力。高水平的CCS可能抑制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是如何解释其促凋亡和抑瘤活性的。为了实现这一目标，首先必须确定CCS与核运输机械部件的相互作用如何导致抑制后者。其次，我们将为CCS抑制核运输在DNA损伤反应中发挥作用的假设寻找证据，并检验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对基因组不稳定发展的影响以及具有抑瘤活性的相关蛋白质的定位来阐明CCS抑瘤活性的分子基础。总体而言，这些研究将描述CCS在正常情况下和DNA损伤后调控核运输方面的作用。他们将确定放松对核运输的管制如何有助于肿瘤形成和细胞凋亡抵抗。在癌症研究中，检测核运输中的肿瘤特异性改变是一种新的方法，CCS为探索这一概念提供了一个独特的靶点。

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.