ROLE OF KAISO IN METASTASIS

描述(摘自申请者的摘要)：E-钙粘素细胞的干扰 已知粘连有助于肿瘤的进展。E-钙粘素下降 在约50%的高转移性癌中完全被调控或丢失。这个 PI已经鉴定出一种新的POZ/ZF转录因子Kaiso，它与 与连环蛋白P120结合。他认为这种蛋白质复合体可能参与了 与b-连环蛋白-Lef1/Tcf相关的信号通路相似，即 在黑色素瘤和结肠癌的进展中起着重要作用。POZ/ZF 一般来说，蛋白质似乎与许多人类癌症有关。这个 等电点的初步数据表明，p120错误地定位于细胞质 E-钙粘附素缺陷型癌的胞核。因此，p120可能本质上是 当不与E-钙粘附素结合时，作为信号分子活跃。此外，推定 Kaiso靶基因已被确定为对存在或 缺乏E-钙粘附素，并具有促进迁移和侵袭性的作用。这个 PI希望检验一个假设，即在E-钙粘附素缺陷细胞中，p120 反式激活Kaiso导致参与的靶基因转录 转移。在目标1中，PI将定义Kaiso和p120在 使用人工启动子/含有亲和力Kaiso的记者转录 DNA结合部位。在AIM 2中，将通过以下方式确定额外的Kaiso目标基因 微阵列技术。公安部主张对小说《凯索》进行鉴定 靶基因应该为Kaiso的作用提供线索，并应该揭示新的 用于阐明信号通路的基因及其启动子 凯索的上游。在目标3中，他描述了以下策略：1)阐明 P120和Kaiso对模型下游Kaiso靶基因转录的调控作用 2)这些发现与转移的生物学特性有关。因此很自然 反映目标规则的启动者/报告者构造将是 用于阐明上游信号通路。然后，路径将是 在明确定义的乳腺癌模型系统的背景下重新评估以 这些发现与促进细胞运动、侵袭的机制直接相关 和转移。拟议中的实验预计将在很大程度上阐明 钙粘素生物学的未知领域，一个可能具有重要意义的领域 以了解转移情况。

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.