Tak1, a novel prostate cancer tumor suppressor

描述（由申请人提供）：TGF β激活激酶1（Tak 1）是由MAP 3 K7基因编码的丝氨酸-苏氨酸激酶。Tak 1是MAP激酶家族的一员，最初被确定为非经典（非Smad）TGF-β 1的下游靶点。信号转导，但现在已知是许多细胞内信号转导途径的中心信号分子，包括白细胞介素1，TNF，Toll和Wnt/β-连环蛋白通路因此，它被认为是一种重要的调节分子，整合了参与生长和分化的多种途径。关于Tak 1在正常前列腺或前列腺癌中的作用知之甚少。我们最近证实了约38%的原发性前列腺肿瘤中存在Tak 1基因座缺失。在同一研究人群中，Tak 1缺失的患病率与PTEN缺失的患病率相当。Tak 1缺失与高Gleason评分显著相关。初步数据支持Tak 1缺失在前列腺肿瘤发生中的作用。由于这些初步的数据和已知的作用，Tak 1作为一个关键的集成器的多个信号从微环境中，我们提出的假设，Tak 1是前列腺癌的肿瘤抑制剂，Tak 1的功能，以调节前列腺上皮细胞的生长和/或分化的微环境。我们将测试这一假设与多学科的方法，结合高通量遗传学与细胞生物学和动物模型研究。提出了三个目标。目的1）Tak 1缺失与Gleason分级的关联;目的2）体内前列腺特异性Tak 1缺失;目的3）肿瘤微环境在Tak 1缺陷中的作用。如果我们的假设是正确的，这些研究是有意义的，因为它们将：1）确定Tak 1缺失与前列腺肿瘤进展预后标志物的关联2）确定Tak 1作为前列腺肿瘤抑制因子3）确定Tak 1在肿瘤微环境中的作用。确定Tak 1在前列腺肿瘤发生中的作用和潜在的基因-基因相互作用也很重要，因为它们可能导致前列腺癌治疗靶向的新策略。公共卫生相关性：前列腺癌是一种致命的疾病，影响美国六分之一的男性。我们已经确定了一个潜在的前列腺癌肿瘤抑制基因位于染色体6 q15，MAP 3 K7基因。我们的研究将测试该基因是否是前列腺癌肿瘤抑制基因，并询问其下游靶点。

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.