Role of the Y-Located TSPY Gene in Human Oncogenesis
Y 定位的 TSPY 基因在人类肿瘤发生中的作用
基本信息
- 批准号:7931856
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-10-01 至 2014-09-30
- 项目状态:已结题
- 来源:
- 关键词:12pAffectAndrogen ReceptorAndrogensAnimal ModelAnimalsApoptoticBindingBinding SitesBiological AssayBiological MarkersCDC2 Protein KinaseCell CycleCell Cycle RegulationCell ProliferationCellsChromosomesChromosomes, Human, YComplexCpG IslandsCultured CellsCyclin BDNADNA Binding DomainDNA MethylationDevelopmentDiagnosticEctopic ExpressionEpigenetic ProcessEtiologyExonsGene ExpressionGene Expression ProfileGene Expression RegulationGene ProteinsGene StructureGene TargetingGenesGenetic PolymorphismGenetic TranscriptionGenomic InstabilityGonadoblastomaGrowthHomologous GeneHormonesHot SpotHumanHuman GenomeLigandsM cellMalignant NeoplasmsMalignant neoplasm of prostateMediatingMethylationMicroarray AnalysisModelingMolecularNodular NeoplasmNormal tissue morphologyNude MiceOncogenesOncogenicOvaryPathogenesisPathway interactionsPhosphotransferasesPhysiologyPlayPrimary carcinoma of the liver cellsProcessPropertyProstaticProstatic TissueProtein BindingProteinsProto-OncogenesRegulationReporterResearchResourcesReverse Transcriptase Polymerase Chain ReactionRoleSex ChromosomesStagingStretchingStructural GenesStructureStructure-Activity RelationshipTesticular Germ Cell TumorTestosteroneTimeTissue RecombinationTransactivationTranscription Repressor/CorepressorTransfectionTransgenesTransgenic MiceTumor Suppressor GenesTumor Suppressor ProteinsTumor TissueVeteransX ChromosomeY Chromosomearmbisulfitecell growthchromatin immunoprecipitationdemethylationdomain mappingearly onsethuman TSPY proteininhibitor/antagonistinsightmalemanmelanomaprogramspromoterprotein structurereceptor functiontherapeutic targettranscription factortransgene expressiontumortumor growthtumorigenesis
项目摘要
DESCRIPTION (provided by applicant):
The testis-specific protein Y-encoded (TSPY) gene is a tandemly repeated gene on the short arm of the human Y chromosome. Its 2.8-kb structural gene is embedded within a 20-kb highly homologous unit that is tandemly repeated up to 64 times, constituting the largest tandem array of functional sequences in the human genome. The TSPY repeats are hot spots for both genomic instability and epigenetic dysregulation on the Y chromosome. TSPY is the proto-oncogene for the gonadoblastoma locus on the Y chromosome (GBY), the only oncogenic locus on this male-specific chromosome. Our research shows that TSPY harbors a conserved protein interacting domain, termed SET/NAP. TSPX is a single-copy TSPY homologue on the X chromosome. Both TSPY and TSPX share significant homologies at both gene organization and protein structure. When ectopically expressed, TSPY and TSPX show contrasting properties in cell cycle regulation. TSPY is ectopically expressed and plays key roles in the initiation and/or progression of gonadoblastoma, testicular germ cell tumors, prostate cancer, and sexual dimorphic cancers, such as hepatocellular carcinoma. TSPY potentiates cell proliferation, accelerates the transition and disrupts the G2/M checkpoints, binds cyclin B and enhances cyclin B-CDK1 kinase activities, and promotes tumor growth in athymic mice. TSPY induces gonadoblastoma-like structure in the ovaries of transgenic mice. TSPX is a tumor suppressor. It binds cyclin B, but represses the cyclin B-CDK1 kinase activity. Ectopic expression of TSPX arrests cells at G2/M stage, and represses tumor growth in athymic mice. We postulate that TSPX serve a normal function in maintaining an orderly cell proliferation and growth while TSPY, when ectopically expressed, counteracts such function(s) and promotes tumorigenesis in susceptible cells. Recently, we have showed that TSPY interacts with androgen receptor (AR) and exacerbates its ligand-dependent transactivation of responsive genes while TSPX interacts but represses AR functions. Hence, TSPY and TSPX could participate in the transcriptional programs mediated by androgen-dependent prostatic oncogenesis. When a TSPY transgene is introduced into the transgenic mouse (LADY) model of prostate cancer, it is ectopically activated at the onset of prostatic oncogenesis in the bi-transgenic mice, resulting in qualitatively more nodular tumors than those from animals without TSPY. These results have provided some important clues and excellent resources for investigating the mechanisms by which TSPY could contribute to prostatic oncogenesis. We will study these problems under three specific aims. First, we plan to elucidate the epigenetic changes associated with TSPY transgene activation during prostatic oncogenesis in the TSPY-LADY bi-transgenic mice, in terms of tumor pathogenesis, transgene expression, DNA methylation status of the TSPY promoter and exon 1, and identification of transcription factors and repressors affected by such epigenetic changes. Second, we will determine the domains responsible for the contrasting functions of TSPY and TSPX on AR transactivation and elucidate the structure-function relationship with a prostatic tissue recombination strategy. Third, we plan to identify and confirm the target genes of a TSPY-AR transcription complex using advanced chromatin immunoprecipitation and promoter tiling microarray (ChIP-Chip) approach. We will determine the transcriptomes of tumors from TSPY-LADY and LADY transgenic mice under normal and hormone-ablated conditions, thereby deducing the genes and pathways mostly affected by an ectopically expressed TSPY transgene in prostatic oncogenesis. We will characterize in details those differentially expressed genes whose promoters are also bound by a TSPY-AR transcriptional complex. The proposed research will provide critical insights on the roles of TSPY and TSPX on prostatic oncogenesis, and translational opportunities in developing diagnostic biomarkers and targets for therapeutic strategies for prostate cancer.
PUBLIC HEALTH RELEVANCE:
Prostate cancer is a prevalent cancer among our veterans. The etiology of this man-only cancer is uncertain. For the past few years, we have examined the functions of a gene on the male-specific chromosome (i.e. Y chromosome) and showed that it contains an oncogene that could promote tumor development in various cancers, including prostate cancer. It has a similar (homologous) gene on the X chromosome that has opposite functions against those of the Y-located oncogene. Hence, the X-gene is a tumor suppressor gene. We show that these two sex chromosome genes can affect testosterone (male-hormone) associated physiology, again in opposing directions. Since testosterone is very important for prostate cancer development and progression, we propose to examine the differences of these two sex chromosome genes in an animal model of prostate cancer. This project will shed important insights on how the Y-oncogene and X-tumor suppressor operate and how one can interfere or boost their actions respectively to treat prostate cancer.
描述(由申请人提供):
睾丸特异性蛋白Y编码基因(Testis-specific protein Y-encoded,TSPY)是位于人类Y染色体短臂上的一个串联重复基因。其2.8 kb的结构基因嵌入在一个20 kb的高度同源单元中,该单元串联重复多达64次,构成了人类基因组中最大的功能序列串联阵列。TSPY重复序列是Y染色体上基因组不稳定性和表观遗传失调的热点。TSPY是Y染色体上性腺母细胞瘤基因座(GBY)的原癌基因,是该男性特异性染色体上唯一的致癌基因座。我们的研究表明,TSPY具有一个保守的蛋白质相互作用结构域,称为SET/NAP。TSPX是X染色体上的单拷贝TSPY同源物。TSPY和TSPX在基因组结构和蛋白质结构上都具有显著的同源性。当异位表达时,TSPY和TSPX在细胞周期调节中显示出相反的特性。TSPY异位表达,并在性腺母细胞瘤、睾丸生殖细胞肿瘤、前列腺癌和性二型癌如肝细胞癌的起始和/或进展中起关键作用。TSPY增强细胞增殖,加速过渡并破坏G2/M检查点,结合细胞周期蛋白B并增强细胞周期蛋白B-CDK 1激酶活性,并促进裸鼠肿瘤生长。TSPY在转基因小鼠卵巢中诱导性腺母细胞瘤样结构。TSPX是一种肿瘤抑制因子。它结合细胞周期蛋白B,但抑制细胞周期蛋白B-CDK 1激酶活性。TSPX的异位表达使细胞停滞在G2/M期,并抑制裸鼠肿瘤生长。我们假设TSPX在维持细胞有序增殖和生长方面发挥正常功能,而TSPY在异位表达时会抵消这种功能并促进易感细胞的肿瘤发生。 最近,我们已经表明,TSPY与雄激素受体(AR)相互作用,并加剧其配体依赖性的反式激活反应基因,而TSPX相互作用,但抑制AR功能。因此,TSPY和TSPX可以参与雄激素依赖性前列腺肿瘤发生介导的转录程序。当TSPY转基因被引入前列腺癌转基因小鼠(LADY)模型时,它在双转基因小鼠前列腺肿瘤发生时被异位激活,导致比没有TSPY的动物产生更多的结节性肿瘤。这些结果为研究TSPY在前列腺肿瘤发生中的作用机制提供了重要的线索和良好的资源。我们将在三个具体目标下研究这些问题。首先,我们计划阐明与TSPY转基因激活前列腺肿瘤发生在TSPY-LADY双转基因小鼠的表观遗传变化,在肿瘤发病机制,转基因表达,DNA甲基化状态的TSPY启动子和外显子1,并确定转录因子和阻遏物的影响,这种表观遗传变化。其次,我们将确定负责TSPY和TSPX对AR反式激活的对比功能的结构域,并阐明与前列腺组织重组策略的结构-功能关系。第三,我们计划使用先进的染色质免疫沉淀和启动子镶嵌微阵列(ChIP-Chip)方法鉴定和确认TSPY-AR转录复合物的靶基因。我们将确定在正常和前列腺切除条件下TSPY-LADY和LADY转基因小鼠肿瘤的转录组,从而推导出在前列腺肿瘤发生中主要受异位表达的TSPY转基因影响的基因和途径。我们将详细描述那些差异表达的基因,其启动子也被TSPY-AR转录复合物结合。这项研究将为TSPY和TSPX在前列腺肿瘤发生中的作用提供重要见解,并为开发前列腺癌诊断生物标志物和治疗策略的靶点提供翻译机会。
公共卫生相关性:
前列腺癌是我们退伍军人中常见的癌症。这种仅限于男性的癌症的病因尚不确定。在过去的几年里,我们已经检查了男性特异性染色体(即Y染色体)上基因的功能,并表明它包含一种致癌基因,可以促进各种癌症(包括前列腺癌)的肿瘤发展。它在X染色体上有一个类似的(同源的)基因,与Y染色体上的癌基因功能相反。因此,X基因是一种肿瘤抑制基因。我们表明,这两个性染色体基因可以影响睾酮(雄性激素)相关的生理,再次在相反的方向。由于睾酮对前列腺癌的发生和发展非常重要,我们建议在前列腺癌动物模型中检查这两种性染色体基因的差异。该项目将对Y癌基因和X肿瘤抑制基因如何运作以及如何分别干扰或增强其作用以治疗前列腺癌提供重要见解。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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YUN-FAI CHRIS LAU其他文献
YUN-FAI CHRIS LAU的其他文献
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