ROLE OF KAISO IN METASTASIS

描述（改编自申请人摘要）：E-钙粘蛋白细胞中的干扰 已知粘附有助于肿瘤进展。E-钙粘蛋白下降 在大约50%的高转移性癌中调节或完全丧失。的 PI已经鉴定了一种新的POZ/ZF转录因子Kaiso， 连环蛋白P120他认为，这种蛋白质复合物可能参与了一种 类似于与b-连环蛋白-Lef 1/TCF相关信号通路， 在黑色素瘤和结肠癌的发展中起着重要作用。POZ/ZF 蛋白质通常似乎与许多人类癌症有关。的 PI的初步数据表明p120错误定位于细胞质 和细胞核。因此，p120可能本质上是 当不与E-钙粘蛋白结合时作为信号分子有活性。此外，假定 已经鉴定了Kaiso靶基因，其响应于存在或不存在Kaiso靶基因。 E-cadherin缺乏，并具有促进迁移和侵袭的作用。的 PI希望检验一个假设，即在E-钙粘蛋白缺陷细胞中，p120 反式激活Kaiso，导致参与的靶基因的转录， 转移在目标1中，PI将定义Kaiso和p120在以下方面的作用： 使用含有亲和Kaiso的人工启动子/报告子的转录 DNA结合位点。在目标2中，将通过以下方法鉴定另外的Kaiso靶基因： 微阵列技术PI认为，新Kaiso的鉴定 靶基因应该为Kaiso的作用提供线索，并揭示新的 基因及其启动子将用于阐明信号通路 在Kaiso的上游在目标3中，他描述了以下策略：1）阐明 p120和Kaiso对下游Kaiso靶点转录的调控作用 基因和2）将发现与转移的生物学相关。如此自然 反映靶调控的启动子/报告子构建体将被 用于阐明上游信号通路。然后，路径将 在明确定义的乳腺癌模型系统的背景下重新评估， 将这些发现直接与促进细胞运动、侵袭 和转移。预计拟议的实验将在很大程度上阐明 钙粘蛋白生物学的未开发领域，一个可能具有重要意义的领域 来理解转移。

DESCRIPTION (Adapt from applicant's abstract): Disturbances in E-cadherin cell adhesion are known to contribute to tumor progression. E-cadherin is down regulated or lost altogether in about 50% of highly metastatic carcinomas. The PI has identified a novel POZ/ZF transcription factor Kaiso that associates with catenin p120. He suggests that this protein complex may be involved in a signal pathway analogous to that associated with b-catenin-Lef1/TCF that figures prominently in the progression of melanoma and colon carcinoma. POZ/ZF proteins in general appear to be involved in numerous human cancers. The preliminary data of the PI indicates that p120 mislocalizes to the cytoplasm and nucleus in E-cadherin deficient carcinomas. Thus p120 may be intrinsically active as a signaling molecule when not bound to E-cadherin. Moreover, putative Kaiso target genes have been identified that are responsive to the presence or absence of E-cadherin and have roles promoting migration and invasiveness. The PI wishes to test a hypothesis that in E-cadherin deficient cells, p120 trans-activates Kaiso leading to transcription of target genes involved in metastasis. In Aim 1 the PI will define the role of Kaiso and p120 in transcription using artificial promotor/reporters containing an affinity Kaiso DNA binding site. In aim 2 additional Kaiso target genes will be identified by microarray technology. The PI contends that identification of novel Kaiso target genes should provide clues to the role of Kaiso and should reveal new genes and their promotors that will be used to elucidate signaling pathways upstream of Kaiso. In aim 3 he describes strategies to 1) elucidate the role of p120 and Kaiso in regulating transcription of a model downstream Kaiso target gene and 2) relate the findings to the biology of metastasis. Thus natural promotor/reporter constructs that reflect the regulation of the target will be used to elucidate upstream signaling pathways. The pathways will then be reevaluated in the context of well-defined breast cancer model systems to relate these findings directly to mechanisms promoting cell motility, invasion and metastasis. The proposed experiments are expected to illuminate a largely unexplored area of cadherin biology, one that may have important implications for understanding metastasis.