Role of ATBF1 inactivation in the development and progression of prostate cancer

ATBF1失活在前列腺癌发生和进展中的作用

基本信息

  • 批准号:
    7031932
  • 负责人:
  • 金额:
    $ 27.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-04-14 至 2011-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The molecular basis of prostate cancer is still poorly understood, and thus identifying and characterizing genes underlying prostate cancer remains an important task. In our preliminary studies, we have identified the ATBF1 transcription factor as a strong candidate for a tumor suppressor gene at the q22 band of chromosome 16 (16q22), one of the most frequently deleted chromosomal regions in prostate cancer (Nature Genetics 2005, in press). We first narrowed the region of deletion at 16q22 to 861-Kb, which contains the ATBF1 gene. We then found that the expression of ATBF1 is at higher levels in normal prostates but is significantly reduced in prostate cancer cells. Furthermore, expression of ATBF1 suppressed cell proliferation or survival. Most notable is that ATBF1 undergoes frequent somatic mutations in human prostate cancer, as 35 mutations of ATBF1 have been detected in 24 of 66 (36%) cancer samples and many of the mutations clearly interrupt ATBF1 function. A 21/24-nucleotide deletion also occurred in the germline of some prostate cancer patients but has not been detected in normal controls. We therefore hypothesize that ATBF1 is a tumor suppressor gene whose loss of function by genomic deletion, mutation, or loss of expression contributes to the development and progression of prostate cancer. This hypothesis is also supported by some published and unpublished studies from other groups. In this proposal, we will further test this hypothesis in four specific aims. First, we will determine if the 21/24-nucleotide deletion of ATBF1 plays a role in human prostate cancer by performing genetic and functional analyses. Second, we will generate a mouse model in which ATBF1 will be specifically knocked out in the prostates of adult mice, and investigate phenotypic alterations resulting from the loss of ATBF1 function. Third, we will examine the role of ATBF1 deletion in prostate cancer in the context of PTEN inactivation, which is also frequently deleted in human prostate cancer. Finally, in aim 4 we will examine if loss of ATBF1 cooperates with loss of NKX3.1 in inducing prostate cancer. The latter is from another frequently deleted chromosomal region in prostate cancer. Completion of these studies will clarify the role of ATBF1 in prostatic carcinogenesis, and will likely present a target that is potentially useful for the diagnosis and prognosis of prostate cancer, as well as for the study of prostate cancer biology.
描述(由申请人提供):前列腺癌的分子基础仍然知之甚少,因此鉴定和表征前列腺癌的潜在基因仍然是一项重要任务。在我们的初步研究中,我们已经鉴定出ATBF 1转录因子是位于16号染色体q22带(16 q22)的肿瘤抑制基因的强有力候选者,16号染色体q22带是前列腺癌中最常缺失的染色体区域之一(Nature Genetics 2005,出版中)。我们首先将16 q22的缺失区域缩小到861-Kb,该区域包含ATBF 1基因。然后,我们发现ATBF 1的表达在正常前列腺中处于较高水平,但在前列腺癌细胞中显著降低。此外,ATBF 1的表达抑制细胞增殖或存活。最值得注意的是,ATBF 1在人类前列腺癌中频繁发生体细胞突变,在66个癌症样本中的24个(36%)中检测到了35个ATBF 1突变,其中许多突变明显中断了ATBF 1功能。21/24核苷酸缺失也发生在一些前列腺癌患者的生殖细胞中,但在正常对照中未检测到。因此,我们假设ATBF 1是一种肿瘤抑制基因,其基因组缺失、突变或表达缺失导致的功能丧失有助于前列腺癌的发生和进展。这一假设也得到了其他研究小组的一些已发表和未发表的研究的支持。在本提案中,我们将在四个具体目标中进一步检验这一假设。首先,我们将通过进行遗传和功能分析来确定ATBF 1的21/24核苷酸缺失是否在人类前列腺癌中起作用。其次,我们将建立一个小鼠模型,其中ATBF 1将在成年小鼠的前列腺中特异性敲除,并研究ATBF 1功能丧失导致的表型改变。第三,我们将研究ATBF 1缺失在前列腺癌中的作用,在PTEN失活的背景下,这也是经常删除在人类前列腺癌。最后,在目标4中,我们将检查ATBF 1的缺失是否与NKX3.1的缺失协同诱导前列腺癌。后者来自前列腺癌中另一个经常缺失的染色体区域。这些研究的完成将阐明ATBF 1在前列腺癌发生中的作用,并可能为前列腺癌的诊断和预后以及前列腺癌生物学研究提供潜在有用的靶点。

项目成果

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JIN-TANG DONG其他文献

JIN-TANG DONG的其他文献

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{{ truncateString('JIN-TANG DONG', 18)}}的其他基金

Bidirectional role of KLF5 in prostatic epithelial homeostasis and tumorigenesis
KLF5 在前列腺上皮稳态和肿瘤发生中的双向作用
  • 批准号:
    8842945
  • 财政年份:
    2013
  • 资助金额:
    $ 27.16万
  • 项目类别:
Bidirectional role of KLF5 in prostatic epithelial homeostasis and tumorigenesis
KLF5 在前列腺上皮稳态和肿瘤发生中的双向作用
  • 批准号:
    9246467
  • 财政年份:
    2013
  • 资助金额:
    $ 27.16万
  • 项目类别:
Bidirectional role of KLF5 in prostatic epithelial homeostasis and tumorigenesis
KLF5 在前列腺上皮稳态和肿瘤发生中的双向作用
  • 批准号:
    8508407
  • 财政年份:
    2013
  • 资助金额:
    $ 27.16万
  • 项目类别:
DEVELOPMENTAL RESEARCH PROGRAM
发展研究计划
  • 批准号:
    7300644
  • 财政年份:
    2007
  • 资助金额:
    $ 27.16万
  • 项目类别:
Role of ATBF1 inactivation in the development and progression of prostate cancer
ATBF1失活在前列腺癌发生和进展中的作用
  • 批准号:
    7597198
  • 财政年份:
    2006
  • 资助金额:
    $ 27.16万
  • 项目类别:
Role of ATBF1 inactivation in the development and progression of prostate cancer
ATBF1失活在前列腺癌发生和进展中的作用
  • 批准号:
    7223401
  • 财政年份:
    2006
  • 资助金额:
    $ 27.16万
  • 项目类别:
Role of ATBF1 inactivation in the development and progression of prostate cancer
ATBF1失活在前列腺癌发生和进展中的作用
  • 批准号:
    7388931
  • 财政年份:
    2006
  • 资助金额:
    $ 27.16万
  • 项目类别:
Role of ATBF1 inactivation in the development and progression of prostate cancer
ATBF1失活在前列腺癌发生和进展中的作用
  • 批准号:
    7784547
  • 财政年份:
    2006
  • 资助金额:
    $ 27.16万
  • 项目类别:
Overexpression of ubiquitin E3 ligase WWP1 as an oncogenic factor in the prostate
泛素 E3 连接酶 WWP1 过度表达作为前列腺致癌因子
  • 批准号:
    7094733
  • 财政年份:
    2000
  • 资助金额:
    $ 27.16万
  • 项目类别:
TUMOR SUPPRESSOR GENE AT 13Q21 IN PROSTATE CANCER
2021 年第 13 季度前列腺癌中的肿瘤抑制基因
  • 批准号:
    6786564
  • 财政年份:
    2000
  • 资助金额:
    $ 27.16万
  • 项目类别:

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