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：
7223401
负责人：
JIN-TANG DONG
金额：
$ 26.37万
依托单位：
EMORY UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/7223401
关键词：
12p12 16q22 8p21 Adult Affect CDKN1A gene CDKN1B gene Cancer Biology Cancer Patient Cell Proliferation Cells Chromosome Deletion Chromosomes, Human, Pair 16 DNA Data Deletion Mutation Development Diagnosis Embryonic Development Epigenetic Process Event Gene Deletion Gene Mutation Gene Targeting Genes Genetic Genomics In Vitro Individual Knock-out Knockout Mice Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Modeling Molecular Mus Mutation NKX3-1 gene Nature Nucleotides Oncogene Proteins PTEN gene Phenotype Play Preneoplastic Change Prostate Prostatic Protein Overexpression Publishing Role Sampling Somatic Mutation Structure of base of prostate Suppressor Genes Testing Transgenic Organisms Tumor Suppressor Genes Tumor Suppressor Proteins age related alpha-Fetoproteins cancer cell cancer diagnosis carcinogenesis cell growth clinically significant cyclin-dependent kinase inhibitor 1B functional loss knockout gene loss of function men mouse model oncoprotein p21 outcome forecast p27 Cell Cycle Protein p27 Enzyme Inhibitor promoter transcription factor tumor

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很少了解，因此确定和表征前列腺癌的基因仍然是一项重要任务。在我们的初步研究中，我们将ATBF1转录因子确定为在Q22染色体16的Q22带（16q22）的肿瘤抑制基因的强候选者，这是前列腺癌中最常见的染色体区域之一（自然遗传学，2005年，印刷中）。我们首先将16q22的缺失区域缩小到包含ATBF1基因的861-KB。然后，我们发现正常前列腺中ATBF1的表达在较高水平，但在前列腺癌细胞中显着降低。此外，ATBF1的表达抑制了细胞增殖或存活。最值得注意的是，ATBF1在人类前列腺癌中经常发生体细胞突变，因为在66个（36％）癌症样本中的24个（36％）中已经检测到35种ATBF1突变，许多突变显然中断了ATBF1功能。一些前列腺癌患者的种系中也发生了21/24-核苷酸缺失，但在正常对照中尚未检测到。因此，我们假设ATBF1是一种肿瘤抑制基因，其基因组缺失，突变或表达丧失的功能丧失有助于前列腺癌的发展和进展。该假设也得到了其他群体的一些已发表和未发表的研究的支持。在此提案中，我们将以四个具体目标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ATBF1的21/24-核苷酸缺失是否在人类前列腺癌中起作用。其次，我们将生成一个小鼠模型，其中ATBF1将在成年小鼠的前列腺中特异性敲定，并研究因ATBF1功能丧失而导致的表型改变。第三，我们将在PTEN失活的背景下检查ATBF1缺失在前列腺癌中的作用，该疾病也经常在人类前列腺癌中删除。最后，在AIM 4中，我们将检查ATBF1在诱导前列腺癌中丧失NKX3.1的损失。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ATBF1在前列腺癌发生中的作用，并可能提出一个可能对前列腺癌的诊断和预后以及前列腺癌生物学研究可能有用的靶标。