Tak1, a novel prostate cancer tumor suppressor

Tak1，一种新型前列腺癌肿瘤抑制因子

• 批准号: 8316493
• 负责人: Scott D Cramer
• 金额: $ 21.24万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316493
• 关键词: Affect; Animal Model; Animals; Apoptosis; BMP4; Cancer Model; Cells; Cellular biology; Characteristics; Chromosomes; Clinical; Crowding; Cues; DNA; Data; Diagnosis; Differentiation and Growth; Disease; Epithelial; Epithelial Cells; Epithelium; Family; Fibrous capsule of kidney; Freezing; Gene Amplification; Gene Deletion; Gene Dosage; Genes; Genetic; Genitourinary system; Gleason Grade for Prostate Cancer; Growth; Health; Heterozygote; Human Genome; Hyperplasia; In Vitro; Interleukin-1; Knockout Mice; Lead; Luciferases; Lymph Node Involvement; MAP kinase kinase kinase 7; MAP3K7 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Methylation; Missense Mutation; Mitogen-Activated Protein Kinases; Modeling; Mutation; Neoplasm Metastasis; Normal tissue morphology; Nuclear Atypia; Nude Mice; Oncogenes; PTEN gene; Pathway interactions; Penetration; Phenotype; Phosphotransferases; Population Study; Prevalence; Prognostic Marker; Proliferating; Proliferation Marker; Prostate; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Protein-Serine-Threonine Kinases; Proteins; Radical Prostatectomy; Recombinants; Role; Sampling; Seminal Vesicles; Serine; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stem cells; Stromal Cells; TNF gene; Testing; Time; Tissue Grafts; Tissue Recombination; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Universities; Weight; cohort; density; fetal; forest; gene interaction; human MAP3K7 protein; in vivo; interdisciplinary approach; male; medical schools; member; men; monolayer; mouse model; neoplastic cell; novel; novel strategies; overexpression; progenitor; promoter; response; stem cell differentiation; therapeutic target; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): TGF beta-activated kinase 1 (Tak1) is a serine-theonine kinase encoded by the MAP3K7 gene. Tak1, a member of the MAP kinase family, was originally identified as a downstream target of non-canonical (non-Smad) TGF-? signaling, but is now known to be a central signaling molecule for a number of intracellular signal transduction pathways, including the interleukin 1, TNF, Toll, and Wnt/?-catenin pathways. As such it is considered an important regulatory molecule that integrates multiple pathways involved in growth and differentiation. Little is known about the role of Tak1 in the normal prostate or in prostate cancer. We recently demonstrated deletion of the Tak1 locus in approximately 38% of primary prostate tumors. The prevalence of Tak1 deletion was equivalent to the prevalence of PTEN deletions in the same study population. There was significant association between loss of Tak1 and high Gleason score. Preliminary data support a role for loss of Tak1 in prostate tumorigenesis. Because of these preliminary data and the known role of Tak1 as a key integrator of multiple signals from the microenvironment, we propose the hypothesis that Tak 1 is a tumor suppresser for prostate cancer and that Tak1 functions to regulate growth and or differentiation of prostate epithelial cells in response to the microenvironment. We will test this hypothesis with a multidisciplinary approach that combines high throughput genetics with cell biology and animal model studies. Three aims are proposed. Aim 1) Association of Tak1 deletion with Gleason Grade; Aim 2) Prostate-Specific Deletion of Tak1 In Vivo; Aim 3) The role of the tumor microenvironment in Tak1 deficiency. If our hypothesis is correct these studies are significant because they will: 1) Determine the association of Tak1 deletion with prostate tumor progression prognostic markers 2) Identify Tak1 as a prostate tumor suppressor 3) Determine the role of Tak1 in the context of the tumor microenvironment. Identification of the role of Tak1 in prostate tumorigenesis and potential gene-gene interactions are also important because they may lead to novel strategies for prostate cancer therapeutic targeting. PUBLIC HEALTH RELEVANCE: Prostate cancer is a deadly disease that affects one in six men in the US. We have identified a potential prostate cancer tumor suppressor gene located on chromosome 6q15, the MAP3K7 gene. Our studies will test if this gene is a prostate cancer tumor suppressor and interrogate its downstream targets.

描述（由申请人提供）：TGFβ激活的激酶1（TAK1）是由MAP3K7基因编码的丝氨酸定义激酶。 TAK1是MAP激酶家族的成员，最初被确定为非典型（非SMAD）TGF-的下游目标？信号传导，但现在已知是许多细胞内信号转导途径的中央信号分子，包括白介素1，TNF，TOLL和WNT/？ - CATENIN途径。因此，它被认为是一个重要的调节分子，它整合了与生长和分化有关的多种途径。关于TAK1在正常前列腺或前列腺癌中的作用知之甚少。我们最近证明了大约38％的原发性前列腺肿瘤中TAK1基因座的缺失。 TAK1缺失的患病率等于同一研究人群中PTEN缺失的普遍性。 TAK1的损失和高格里森评分之间存在显着关联。初步数据支持在前列腺肿瘤发生中丢失TAK1的作用。由于这些初步数据以及TAK1作为微环境的多个信号的关键集成剂的已知作用，我们提出了以下假设：TAK 1是前列腺癌的肿瘤抑制剂，并且TAK1在对微环境的响应响应前列腺上皮细胞的生长和或分化的作用。我们将使用多学科方法来检验该假设，该方法将高通量遗传学与细胞生物学和动物模型研究结合在一起。提出了三个目标。目标1）TAK1删除与格里森等级的关联；目标2）体内Tak1的前列腺特异性缺失；目标3）肿瘤微环境在TAK1缺乏症中的作用。如果我们的假设是正确的，这些研究很重要，因为它们将：1）确定TAK1删除与前列腺肿瘤进展的预后标志物的关联2）将TAK1识别为前列腺肿瘤抑制剂3）在肿瘤微环境的背景下确定TAK1的作用。 TAK1在前列腺肿瘤发生和潜在基因相互作用中的作用的鉴定也很重要，因为它们可能导致前列腺癌治疗靶向的新型策略。公共卫生相关性：前列腺癌是一种致命疾病，影响了美国六分之一。我们已经确定了位于MAP3K7基因6q15染色体上的潜在前列腺癌抑制基因。我们的研究将测试该基因是否是前列腺癌肿瘤抑制剂，并询问其下游靶标。