Nuclear Transport Factors in Chromosomal Instability
染色体不稳定性中的核运输因素
基本信息
- 批准号:6700871
- 负责人:
- 金额:$ 30.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-04-01 至 2008-01-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Most human cancers are characterized by chromosome number alterations. Molecular defects that initiate or promote losses or gains of whole chromosomes remain largely unknown. In some cancers with chromosomal instability, mutations have been identified in genes that encode for mitotic checkpoint proteins, such as Bub1 BubR1 and Mad2. These proteins are parts of an intricate molecular machine that blocks the onset of anaphase until all chromosomes are properly attached to the mitotic spindle apparatus and aligned at the metaphase plate. Following disassembly of the nuclear envelope at mitosis, the nucleocytoplasmic transport factors Ran and importin alpha/beta become key regulators of mitotic spindle assembly. Nup98, another nuclear transport factor, is a frequent target of genetic alterations in acute leukemias. Nup98 contains a motif, termed GLEBS, that directs binding to the putative mRNA export factor Rae1. We have recently shown that a GLEBS motif is present in the mitotic checkpoint proteins Bub1 and BubR1, where it serves as a binding site for the Rae1-related mitotic checkpoint protein Bub3. Using a gene-knockout approach, we have determined that Nup98 and Rae1 not only share sequence homology with Bub proteins, but are required for mitotic checkpoint function as well. The overall goal of this proposal is to define the role of Nup98 and its binding partner Rae1 in the maintenance of chromosomal stability and tumor formation. In the first aim, we will determine the mechanism by which Nup98 regulates mitotic checkpoint function and chromosomal stability. In the second aim, we will examine the role of Nup98 in normal and neoplastic growth by tissue-specific disruption of Nup98 in mice. In the third aim, we will focus on the role of Rae1 in mitotic checkpoint function, maintenance of chromosomal stability, and tumor formation. Information gained from these studies will provide a framework for understanding the mechanisms by which nuclear transport factors contribute to genetic instability and cancer.
描述(由申请人提供):大多数人类癌症的特征是染色体数目改变。引发或促进整个染色体丢失或获得的分子缺陷在很大程度上仍然未知。在一些具有染色体不稳定性的癌症中,已经在编码有丝分裂检查点蛋白的基因中鉴定出突变,例如Bub 1 BubR 1和Mad 2。这些蛋白质是一个复杂的分子机器的一部分,它阻止了后期的开始,直到所有的染色体都正确地附着在有丝分裂的纺锤体上,并在中期板上排列。在有丝分裂核膜解体后,核质转运因子Ran和importin α/β成为有丝分裂纺锤体组装的关键调节因子。Nup 98是另一种核转运因子,是急性白血病遗传变异的常见靶点。Nup 98含有一个称为GLEBS的基序,该基序指导与推定的mRNA输出因子Rae 1结合。 我们最近发现,GLEBS基序存在于有丝分裂检查点蛋白Bub 1和BubR 1中,在那里它作为Rae 1相关的有丝分裂检查点蛋白Bub 3的结合位点。使用基因敲除方法,我们已经确定Nup 98和Rae 1不仅与Bub蛋白共享序列同源性,而且也是有丝分裂检查点功能所需的。该提案的总体目标是确定Nup 98及其结合伴侣Rae 1在维持染色体稳定性和肿瘤形成中的作用。在第一个目标中,我们将确定Nup 98调节有丝分裂检查点功能和染色体稳定性的机制。在第二个目标中,我们将通过小鼠中Nup 98的组织特异性破坏来检查Nup 98在正常和肿瘤生长中的作用。在第三个目标中,我们将关注Rae 1在有丝分裂检查点功能,染色体稳定性维护和肿瘤形成中的作用。从这些研究中获得的信息将为理解核转运因子导致遗传不稳定和癌症的机制提供一个框架。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JAN M. VAN DEURSEN其他文献
JAN M. VAN DEURSEN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JAN M. VAN DEURSEN', 18)}}的其他基金
Bub 1 in Chromosomal Instability and Tumorigenesis
Bub 1 在染色体不稳定性和肿瘤发生中的作用
- 批准号:
7242409 - 财政年份:2007
- 资助金额:
$ 30.88万 - 项目类别:
Nuclear Transport Factors in Chromosomal Instability
染色体不稳定性中的核运输因素
- 批准号:
6850792 - 财政年份:1998
- 资助金额:
$ 30.88万 - 项目类别:
相似海外基金
Long-Acting VEGF Binding Proteins for Treating Cancer
用于治疗癌症的长效 VEGF 结合蛋白
- 批准号:
6784974 - 财政年份:2004
- 资助金额:
$ 30.88万 - 项目类别:
NMR Studies of Retroviral Nucleic Acid Binding Proteins
逆转录病毒核酸结合蛋白的 NMR 研究
- 批准号:
6797462 - 财政年份:1989
- 资助金额:
$ 30.88万 - 项目类别:
NMR Studies of Retroviral Nucleic Acid Binding Proteins
逆转录病毒核酸结合蛋白的 NMR 研究
- 批准号:
6851802 - 财政年份:1989
- 资助金额:
$ 30.88万 - 项目类别:
NMR Studies of Retroviral Nucleic Acid Binding Proteins
逆转录病毒核酸结合蛋白的 NMR 研究
- 批准号:
6711203 - 财政年份:1989
- 资助金额:
$ 30.88万 - 项目类别:
NMR Studies of Retroviral Nucleic Acid Binding Proteins
逆转录病毒核酸结合蛋白的 NMR 研究
- 批准号:
6627820 - 财政年份:1989
- 资助金额:
$ 30.88万 - 项目类别:
NMR Studies of Retroviral Nucleic Acid Binding Proteins
逆转录病毒核酸结合蛋白的 NMR 研究
- 批准号:
6496425 - 财政年份:1989
- 资助金额:
$ 30.88万 - 项目类别:
STRUCTURE AND FUNCTION OF B12-BINDING PROTEINS
B12 结合蛋白的结构和功能
- 批准号:
3483386 - 财政年份:1977
- 资助金额:
$ 30.88万 - 项目类别:
STRUCTURE AND FUNCTION OF B12-BINDING PROTEINS
B12 结合蛋白的结构和功能
- 批准号:
3483388 - 财政年份:1977
- 资助金额:
$ 30.88万 - 项目类别:
STRUCTURE AND FUNCTION OF B12-BINDING PROTEINS
B12 结合蛋白的结构和功能
- 批准号:
3483389 - 财政年份:1977
- 资助金额:
$ 30.88万 - 项目类别:
STRUCTURE AND FUNCTION OF B12-BINDING PROTEINS
B12 结合蛋白的结构和功能
- 批准号:
3483390 - 财政年份:1977
- 资助金额:
$ 30.88万 - 项目类别: