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

描述（由申请人提供）：mapk调节细胞生长、分化和应激反应，许多关键的信号通路受到MARK信号传导的交叉调节。先前的研究已经证实了MARK通路和雄激素受体（AR）信号之间的串扰，这在正常前列腺和前列腺癌的生长控制中都起着关键作用。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，NLK显著抑制ar介导的信号传导并最终刺激CaP细胞凋亡。本项目的目的是阐明NLK对前列腺细胞AR信号传导的作用机制，并评估其作为新的治疗靶点的前景。我们将进行NLK与AR相互作用的机制研究，包括转录分析、蛋白水平修饰和辅因子关联。我们还将研究NLK在前列腺细胞中的促凋亡作用及其与AR信号抑制的关系，并利用我们先进的动物模型研究NLK在体内的作用。更深入地了解NLK在前列腺癌进展中的作用、ar定向转录的调控及其生物学效应，将有助于认识在CaP中重构功能性NLK信号的价值，并为这种疾病的治疗干预指明新模式。本研究的具体目的是阐明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:

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.