RKIP regulation as a potential for tumor suppression

本研究的重点是阐明Raf激酶抑制蛋白RKIP的功能，RKIP是一种新的激酶抑制蛋白 该基因在体外被确认为一种有效的肿瘤转移抑制因子，其转录调控通过 Snail和/或EZH2(Zust Homolog 2的增强子)-我们的假设是理解信号转导的关键 前列腺癌进展和转移的途径。从机制上讲，这种蛋白质的功能是 Raf和NF-B信号通路的负调节因子。与其对这些基因的抑制作用相一致 RKIP的表达与肿瘤分期呈显著负相关。 前列腺癌的癌变。特别是，在健康的前列腺组织中发现了高水平的RKIP， 而这些水平在前列腺组织中逐渐下降到几乎检测不到的水平 进攻性和转移能力。重要的是，在高转移性肿瘤中恢复RKIP的表达 前列腺癌细胞系在异种移植小鼠模型中使其对凋亡敏感并抑制转移， 这表明这种蛋白质是一种很有前途的癌症治疗候选蛋白。为了利用这一潜力， 本申请提出定义调节RKIP表达的转录因子(特异性 目的1)，并建立其在体内的生理相关性(特定目的2)。特别是，具体目标#1将 研究转录因子Snail和EZH2在调控RKIP表达中的可能作用 前列腺癌。这将通过功能损失和功能获得两种方法以及通过 一种遗传和生化方法的结合。具体目标#2将研究蜗牛在体内可能的作用 和EZH2作为RKIP在前列腺癌中表达的调节，使用DNA和组织芯片(TMA) RKIP与上述两种转录因子表达的相关性研究 前列腺癌患者的样本。前列腺癌是最常见的恶性肿瘤。 美国的男性。这一建议应该为从分子细节上理解其病因提供一个新的视角。 并启动旨在剖析复杂调控转录网络的研究 下调RKIP的监管。从这项研究中获得的信息为两者提供了一个很有希望的潜力 前列腺癌治疗，以及其他癌症。

This proposal focuses on elucidating the function of Raf Kinase Inhibitor Protein, RKIP, a novel kinase inhibitor that was identified as a potent tumor metastasis suppressor in vitro, and whose transcription regulation – by Snail and/or EZH2 (Enhancer of Zeste Homolog 2) – we hypothesize is key to understanding signaling pathways involved in prostate cancer progression and metastasis. Mechanistically, this protein functions as a negative regulator of both the Raf and NF-_B signaling pathways. Consistent with its inhibitory effects on these two pathways, a significant inverse correlation was observed between the expression of RKIP and the stage of cancer development in prostate tumors. Particularly, high levels of RKIP were noted in healthy prostate tissue, whereas these levels progressively decreased to almost undetectable levels in prostate tissues of increasing aggressiveness and metastatic capability. Importantly, restoration of RKIP expression in highly metastatic prostate cancer cell lines sensitized them to apoptosis and inhibited metastasis in a xenograft mouse model, suggesting this protein as a promising candidate for cancer therapy. In order to utilize this potential, the present application proposes to define the transcription factors that regulate RKIP expression (Specific Aim #1) and establish its physiological relevance in vivo (Specific Aim #2). Particularly, Specific Aim #1 will examine the possible roles of the transcription factors Snail and EZH2 in regulating RKIP expression in prostate cancer. This will be done by both loss-of-function and gain-of-function approaches, as well as through a combination of genetic and biochemical methods. Specific Aim #2 will study a possible in vivo role of Snail and EZH2 as regulators of RKIP expression in prostate cancer, using DNA and tissue microarray (TMA) studies to correlate between the expression of RKIP and the two abovementioned transcription factors in samples from prostate cancer patients. Carcinoma of the prostate is the most common malignancy among males in the US. This proposal should provide a new handle for understanding its etiology in molecular detail and initiate studies aimed at dissecting the complex regulatory transcriptional network that is responsible for downregulation of RKIP. The information gained from this research offers a promising potential for both prostate cancer therapy, as well as other cancers.