MECHANISMS OF P27KIPL-ASSOCIATED NEOPLASIA

该提案的总体目标是表征p27 kip 1蛋白的正常调节，以及这种调节的丧失如何有助于多步骤肿瘤发生。p27 kip 1是细胞周期蛋白依赖性激酶（CDK）抑制剂的Cip/Kip家族的成员，其结合至响应于抗增殖信号的抑制CDK。P27的表达受有丝分裂原等生理刺激的调节。相反，p27表达的缺失与细胞分裂和肿瘤发生的增加有关。p27低表达与细胞分裂增加和肿瘤发生有关。p27低表达与许多人类癌症的不良结局相关，并且p27在小鼠中起肿瘤抑制剂的作用。肿瘤中p27丢失的机制以及它如何参与肿瘤转化在很大程度上是未知的。本提案中所述的实验解决了这两个问题。P27丰度在许多水平上受到控制，包括蛋白水解、翻译、磷酸化和亚细胞定位。在本提案中，我们将定义p27的核转运机制，以及它们如何与其他p27控制模式相结合，以全面调节p27的丰度和功能。我们已经确定了一种新的核孔蛋白，称为PASSTA，它与p27相互作用，并在小鼠中产生PASSTA的靶向缺失，导致胚胎死亡，神经管缺陷和侏儒症。我们现在将检验PASSTA介导p27和核孔之间相互作用的假设，并确定这些相互作用在正常和肿瘤细胞中的机制和生理后果。p27抑制肿瘤的机制尚不清楚。我们已经建立了一个小鼠模型，以确定在多步骤中与p27丢失合作的基因。 通过使用插入诱变在p27缺失和野生型小鼠中诱导淋巴瘤来进行转化。P27无效动物表现出极大加速的淋巴细胞生成。我们现在将确定这些淋巴瘤中的激活基因，确定它们如何与p27丢失协同作用，并检查它们是否与p27低表达相关的人类癌症相似。最终，了解p27在正常和肿瘤细胞中的调节机制可能会导致识别用于治疗癌症和其他疾病的新的治疗靶点。

The overall goal of this proposal is to characterize the normal regulation of the p27 kip1 protein, and how loss of this regulation contributes to multi-step tumorigenesis. p27kip1 is a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors, which bind to an inhibit CDKs in response to anti-proliferative signals. P27 expression is regulated by physiologic stimuli such as mitogen. Conversely, loss of p27 expression is associated with increased cell division and tumorigenesis. Low p27 expression is associated with increased cell division and tumorigenesis. Low p27 expression correlates with poor outcome in many human cancers, and p27 function as a tumor suppressor in mice. The mechanism of p27 loss in tumors and how this participates in neoplastic transformation is largely unknown. The experiments described in this proposal address both of these issues. P27 abundance is controlled at many levels, including proteolysis, translation, phosphorylation, and subcellular localization. In this proposal, we will define the nuclear transport mechanisms of p27, and how they are integrated with other modes of p27 control to globally regulate p27 abundance and function. We have identified a novel nuclear pore protein, termed PASSTA, that interacts with p27 and created a targeted deletion of PASSTA in mice that causes embryonic lethality, neural tube defects, and dwarfism. We will now test the hypothesis that PASSTA mediates interactions between p27 and the nuclear pore, and determine the mechanisms and physiologic consequences of these interactions in normal and tumor cells. The mechanism of tumor suppression by p27 is not clearly understood. We have established a mouse model to identify genes that cooperate with p27 loss in multi-step transformations by using insertional mutagenesis to induce lymphomas in p27 null and wild type mice. P27 null animals exhibit greatly accelerated lymphogenesis. We will now identify the activated genes in these lymphomas, determine how they synergize with p27 loss, and examine if they are similarly involved with human cancer associated with low p27 expression. Ultimately, understanding the mechanisms underlying p27 regulation in normal and neoplastic cells may lead to the identification of novel therapeutic targets for the treatment of cancer and other diseases.