STRUCTURE AND FUNCTION OF CTCF--TRANSGENIC MICE STUDIES
CTCF的结构和功能--转基因小鼠研究
基本信息
- 批准号:6512768
- 负责人:
- 金额:$ 42.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-06-05 至 2003-08-31
- 项目状态:已结题
- 来源:
- 关键词:breast neoplasms chemical carcinogenesis dimethylbenzanthracene gene mutation genetic promoter element genetically modified animals immunocytochemistry laboratory mouse neoplasm /cancer genetics northern blottings nucleic acid sequence polymerase chain reaction protein structure function protooncogene radiation carcinogen radiation carcinogenesis single strand conformation polymorphism southern blotting tissue /cell culture transcription factor tumor suppressor genes western blottings
项目摘要
DESCRIPTION: (Adapted from the investigator's abstract) CTCF is an
evolutionarily conserved 11 Zinc finger (ZF) transcription factor with multiple
DNA sequence specificity. CTCF-target sites are found in promoters of several
genes including c-myc, Polo-like kinase and Pim-1 oncogenes. Normally, it
negatively regulates cell proliferation. The CTCF gene is localized at the
human chromosome locus 16q22.1 within a region that displays frequent
cancer-associated deletions. Our mutational analysis of CTCF revealed several
tumor-specific mutations resulting in amino acid substitutions at different
positions critical either for ZF formation or for DNA base recognition. Each
mutation selectively eliminates CTCF binding to some but not to all target DNA
sites, suggesting that the oncogenic potential of mutant CTCF proteins may
result from shifting the spectrum of target genes regulated by CTCF. These
findings provide the first evidence for role of CTCF as a candidate tumor
suppressor gene at 16q22.
However, the most convincing experimental approach to demonstrate a
CTCF-mediated cancer phenotype would be an observation of enhanced tumor
susceptibility in CTCF deficient mice. Our preliminary results conclusively
demonstrate that CTCF (+/-) knockout mice are predisposed to tumor development
in multiple tissues compared to wild type littermates. Therefore, based on our
experience with the p53 and p27 (Kip1) deficient mice, we plan to expand
analyses of CTCF(+/-) mice to study in detail effects of CTCF
haplo-insufficiency on spontaneous, radiation-, ENU-, DMBA-, and other
carcinogens- induced tumor predisposition. There appears to be no tissue or a
cell line negative for CTCF-containing RNA message(s). Homologous knockout of
CTCF in transgenic mice results in early embryonic lethality. Therefore,
complete loss of CTCF function in cancer is unlikely because it may be
incompatible with cell proliferation. This hypothesis will be tested by
analyzing mechanisms of inactivation of the remaining wild type CTCF allele
(mutations and/or altered expression) in tumors developing from different
tissues in irradiated or carcinogen- challenged CTCF (+/-) mice. In addition,
we will test whether CTCF null mutation results in preimplantation lethality
that may be expected if TCF has "cell-autonomous" essential, and universal
function. We also anticipate genetic crosses to other tumor-prone mice such as
p53 and p27 deficient mice to reveal genetic pathways, which cooperate with
CTCF deficiency in normal development and tumorigenesis.
描述:(改编自调查人员的摘要)CTCF是一种
进化保守的11个锌指(ZF)转录因子
DNA序列特异性。CTCF-靶点在几个启动子中被发现
基因包括c-myc、Polo样激酶和Pim-1癌基因。正常情况下,它
负向调节细胞增殖。CTCF基因定位于
人类染色体16q22.1基因座在一个显示频繁的区域内
与癌症相关的缺失。我们对CTCF的突变分析揭示了几个
肿瘤特异性突变导致不同部位的氨基酸替换
ZF形成或DNA碱基识别的关键位置。每个人
突变选择性地消除CTCF与部分但不是全部靶DNA的结合
位点,提示突变的CTCF蛋白的致癌潜力可能
这是由于CTCF调控的靶基因谱发生变化而产生的。这些
这些发现为CTCF作为候选肿瘤的作用提供了第一个证据
抑癌基因位于16q22。
然而,最有说服力的实验方法来演示
CTCF介导的肿瘤表型将是肿瘤增强的观察
CTCF缺陷小鼠的易感性。我们的初步结果是决定性的
证明CTCF(+/-)基因敲除小鼠易患肿瘤
与野生型窝产仔相比,在多种组织中。因此,基于我们的
对于p53和p27(Kip1)缺陷小鼠的经验,我们计划扩大
通过对CTCF(+/-)小鼠的分析研究CTCF的作用
自发性、辐射性、ENU-、DMBA-等单纯性不足
致癌物诱导的肿瘤易感性。看起来没有纸巾或者是
含CTCFRNA信息阴性的细胞系(S)。同源基因敲除
转基因小鼠的CTCF可导致早期胚胎死亡。因此,
癌症中CTCF功能完全丧失的可能性不大,因为它可能是
与细胞增殖不相容。这一假设将通过以下方式检验
剩余野生型CTCF等位基因失活机制分析
(突变和/或表达改变)在不同来源的肿瘤中
照射或致癌物激发的CTCF(+/-)小鼠的组织。此外,
我们将测试CTCF零突变是否会导致植入前死亡
如果TCF具有“细胞自主”的本质和普适性,那么这是可以预料到的
功能。我们还预计与其他易患肿瘤的小鼠进行基因杂交,如
P53和p27缺陷小鼠揭示基因途径,这些途径与
CTCF缺乏在正常发育和肿瘤发生中的作用
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)
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{{ truncateString('GALINA N FILIPPOVA', 18)}}的其他基金
Role of CTCF in Chromatin and Nuclear Organization at the FSHD 4qD4Z4Locus
CTCF 在 FSHD 4qD4Z4 位点染色质和核组织中的作用
- 批准号:
8232182 - 财政年份:2011
- 资助金额:
$ 42.7万 - 项目类别:
Structure and Function of CTCF: Mouse Model Studies
CTCF的结构和功能:小鼠模型研究
- 批准号:
6680238 - 财政年份:1996
- 资助金额:
$ 42.7万 - 项目类别:
Structure and Function of CTCF: Mouse Model Studies
CTCF的结构和功能:小鼠模型研究
- 批准号:
6930414 - 财政年份:1996
- 资助金额:
$ 42.7万 - 项目类别:
Structure and Function of CTCF: Mouse Model Studies
CTCF的结构和功能:小鼠模型研究
- 批准号:
6769422 - 财政年份:1996
- 资助金额:
$ 42.7万 - 项目类别:
STRUCTURE AND FUNCTION OF CTCF--TRANSGENIC MICE STUDIES
CTCF的结构和功能--转基因小鼠研究
- 批准号:
6376175 - 财政年份:1996
- 资助金额:
$ 42.7万 - 项目类别:
Structure and Function of CTCF: Mouse Model Studies
CTCF的结构和功能:小鼠模型研究
- 批准号:
7118531 - 财政年份:1996
- 资助金额:
$ 42.7万 - 项目类别:
Structure and Function of CTCF: Mouse Model Studies
CTCF的结构和功能:小鼠模型研究
- 批准号:
7253908 - 财政年份:1996
- 资助金额:
$ 42.7万 - 项目类别:
STRUCTURE AND FUNCTION OF CTCF--TRANSGENIC MICE STUDIES
CTCF的结构和功能--转基因小鼠研究
- 批准号:
6126596 - 财政年份:1996
- 资助金额:
$ 42.7万 - 项目类别:
MUTATIONS OF CTCF GENE AT CANCER ASSOCIATED LOCUS 16Q22
CTCF 基因在癌症相关位点 16Q22 的突变
- 批准号:
2733263 - 财政年份:1996
- 资助金额:
$ 42.7万 - 项目类别:
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