Regulation and function of the YAP transcription co-activator oncoprotein

描述（由申请人提供）：雅普转录辅激活子癌蛋白的调节和功能 yes相关蛋白雅普是一种有效的转录辅激活因子。最近的遗传学研究表明雅普是人类染色体11 q22扩增子中的一个候选癌基因。果蝇的研究已经建立了一种新的肿瘤抑制途径Hippo，它调节细胞增殖和凋亡。Hippo途径的许多组分是高度保守的。雅普可能是Hippo通路抑制的主要靶点。雅普可以在果蝇中功能性地拯救yorkie（哺乳动物雅普的果蝇同源物）突变。已经提出神经纤维瘤病2（NF 2）肿瘤抑制因子是Hippo通路的组分，其作用于雅普的上游以抑制雅普功能。然而，尚未在哺乳动物细胞中研究Hippo途径。该项目的长期目标是确定Hippo通路在人类癌症发展中的功能和调节。我们的初步数据表明，Hippo-YAP通路在细胞接触抑制和致癌转化中起着重要作用。此外，雅普在人类癌症（包括前列腺癌和肝癌）中高度升高。这项建议的具体目标是： 1.鉴定和表征雅普靶转录因子 2.确定雅普靶转录因子在细胞接触抑制、致癌转化和上皮-间质转化中的功能 3.确定YAP诱导的微小RNA的功能 公共卫生相关性：雅普是一种转录辅激活因子和致癌基因，在人类癌症中高度升高。本研究拟从分子水平探讨雅普通过促进细胞增殖和抑制细胞死亡参与肿瘤发生的机制。

DESCRIPTION (provided by applicant): Regulation and function of the YAP transcription co-activator oncoprotein The yes-associated protein YAP is a potent transcription co-activator. Recent genetic studies have implicated YAP as a candidate oncogene in human chromosome 11q22 amplicon. Drosophila studies have established a novel tumor suppressor pathway Hippo that regulates both cell proliferation and apoptosis. Many components of the Hippo pathway are highly conserved. YAP is likely to be the major target inhibited by the Hippo pathway. YAP can functionally rescue yorkie (the Drosophila homolog of mammalian YAP) mutation in Drosophila. It has been suggested that the neurofibromatosis 2 (NF2) tumor suppressor is a component of the Hippo pathway acting upstream of YAP to inhibit YAP function. However, the Hippo pathway has not been investigated in mammalian cells. The long term goals of this project are to determine the function and regulation of the Hippo pathway in development of human cancers. Our preliminary data have shown that the Hippo-YAP pathway plays an essential role in cell contact inhibition and oncogenic transformation. Furthermore, YAP is highly elevated in human cancers, including prostate and liver cancers. The specific aims of this proposal are: 1. To identify and characterize YAP target transcription factors 2. To determine the function of YAP target transcription factors in cell contact inhibition, oncogenic transformation, and epithelial-mesenchymal transition 3. To determine the function of YAP-induced micro RNA Public Health Relevance: YAP is a transcription co-activator and oncogene highly elevated in human cancers. This proposal will study the molecular mechanism of YAP in tumorigenesis by promoting cell proliferation and inhibiting cell death.