Roles of Nemo-like kinase in CaP and its effects on androgen receptor signaling

Nemo 样激酶在 CaP 中的作用及其对雄激素受体信号传导的影响

基本信息

批准号：
7315784
负责人：
EVA COREY
金额：
$ 23.71万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-10 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7315784
关键词：
Androgen Receptor Androgens Animal Model Apoptosis Biological Biological Assay Cell Communication Cell Cycle Cells Clinical Colon Carcinoma Data Depth Detection Development Disease Disease Progression EMSA Environment Epithelial Cells Epithelium Flow Cytometry Genetic Transcription Goals Growth Health Immunoprecipitation In Vitro Induction of Apoptosis LNCaP Lead MAP Kinase Gene Malignant neoplasm of prostate Mass Spectrum Analysis Mediating Methods Modification Molecular Biology Nature Neoplasm Metastasis Pathway interactions Patients Phosphotransferases Play Population Process Prognostic Marker Prostate Prostatic Neoplasms Protein Analysis Protein Chemistry Protein Overexpression Proteins Receptor Signaling Regulation Reporter Research Personnel Resistance Role Sampling Signal Pathway Signal Transduction System Therapeutic Therapeutic Intervention Transfection androgen independent prostate cancer base biological adaptation to stress bone cancer cell cell growth cofactor cohort design in vitro Model in vivo insight killings neoplastic cell novel novel therapeutics programs promoter reconstitution research study subcutaneous therapeutic target tumor tumor progression yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The MAPKs regulate cell growth, differentiation, and stress responses, and many critical signaling pathways are subject to cross-regulation by MARK signaling. Previous studies have yielded evidence of crosstalk between the MARK pathways and androgen receptor (AR) signaling, which plays a critical role in growth control of both normal prostate and prostate cancer. We have shown that the MAPK-like protein, Nemo-like kinase (NLK) expression is altered during prostate cancer progression, and that NLK dramatically inhibits AR-mediated signaling and ultimately stimulating apoptosis in CaP cells. The goal of this project is to elucidate the mechanisms of NLK effects on AR signaling in prostate cells and to evaluate its promise as a new therapeutic target. We will perform mechanistic studies on interaction of NLK with AR, including transcriptional analysis and protein-level modifications, and cofactors associations. We will also investigate the proapoptotic effects of NLK in prostate cells and its relation to inhibition of AR signaling, and study in vivo effects of NLK using our advanced animal models. A deeper understanding of the NLK roles in prostate cancer progression and regulation of AR-directed transcription and its biological effects will lead to an appreciation of the value of reconstituting functional NLK signaling in CaP and point the way to new modes of therapeutic intervention in this disease. The specific aims of this proposal are intended to elucidate the nature and mechanisms of induction of apoptosis in CaP cells by NLK and characterize the effects of NLK expression on critical signaling pathways in these cells. Specific aims: 1) To investigate associations of NLK expression with clinical parameters of prostate cancer. 2) To investigate the mechanisms of NLK effects on AR-directed transcription. 3) To investigate the mechanisms whereby NLK promotes apoptosis of CaP cells. 4) To investigate the effects of NLK expression on prostate cancer tumors in vivo. Health relevance: Advanced prostate cancer is a devastating, fatal, and almost untreatable disease. By studying the ability of nemo-like kinase to kill even prostate-cancer cells that are resistant to other treatments, we hope to point the way to new and promising therapeutic approaches for advanced prostate cancer.

描述（由申请人提供）：MAPK 调节细胞生长、分化和应激反应，许多关键信号传导途径受到 MARK 信号传导的交叉调节。先前的研究已经证明 MARK 通路和雄激素受体 (AR) 信号之间存在串扰，这在正常前列腺和前列腺癌的生长控制中发挥着关键作用。我们已经证明，MAPK 样蛋白、Nemo 样激酶 (NLK) 的表达在前列腺癌进展过程中发生改变，并且 NLK 显着抑制 AR 介导的信号传导并最终刺激 CaP 细胞凋亡。该项目的目标是阐明 NLK 对前列腺细胞 AR 信号传导的影响机制，并评估其作为新治疗靶点的前景。我们将对 NLK 与 AR 的相互作用进行机制研究，包括转录分析和蛋白质水平修饰以及辅因子关联。我们还将研究 NLK 在前列腺细胞中的促凋亡作用及其与 AR 信号传导抑制的关系，并使用我们先进的动物模型研究 NLK 的体内作用。更深入地了解 NLK 在前列腺癌进展中的作用以及 AR 定向转录的调节及其生物学效应，将有助于认识到在 CaP 中重建功能性 NLK 信号传导的价值，并为该疾病的治疗干预新模式指明道路。。该提案的具体目的是阐明 NLK 诱导 CaP 细胞凋亡的性质和机制，并表征 NLK 表达对这些细胞中关键信号通路的影响。具体目标： 1）研究NLK表达与前列腺癌临床参数的关联。 2)研究NLK影响AR定向转录的机制。 3)探讨NLK促进CaP细胞凋亡的机制。 4)研究NLK表达对体内前列腺癌肿瘤的影响。健康相关性：晚期前列腺癌是一种毁灭性、致命性且几乎无法治愈的疾病。通过研究尼莫样激酶甚至杀死对其他治疗有抵抗力的前列腺癌细胞的能力，我们希望为晚期前列腺癌的新的和有前途的治疗方法指明道路。