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.
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