Cell Autonomy and Tumor Suppression by CDK inhibitors

描述(由申请人提供)：细胞周期生长抑制剂抑制肿瘤的模型通常假设关键的抑制活性是肿瘤克隆所固有的。最近在小鼠模型中发现的肿瘤抑制基因不能完全抑制肿瘤生长，只丢失一个基因拷贝(即单倍体肿瘤抑制不足)，这增加了替代的、非细胞自主的肿瘤抑制机制的可能性。例如，在肿瘤克隆外的细胞中，细胞周期抑制物表达的缺失可能通过细胞外接触、旁分泌因子或血管生成介导的信号来促进细胞生长。 这个项目将进一步加深我们对CDK抑制剂p27Kipl和几个相互作用的分子抑制肿瘤机制的理解。这些研究将在小鼠身上产生有针对性的突变，其中p27在特定组织中被删除或激活。然后，这些新的基因突变将与明确的诱导致癌小鼠模型和基因表达分析相结合，以确定p27的肿瘤抑制机制及其在肿瘤发生中的生化作用。 通过将细胞周期基因突变局限于垂体或胸腺的小鼠的发育，将确定p27Kip 1是否能够以细胞自主的方式诱导这些组织中的腺瘤和淋巴瘤，这与周围细胞或组织的因素的影响无关。在每个模型系统中，将进一步确定p27抑制肿瘤的机制，并将表征改变的基因表达和细胞周期蛋白功能的模式。 为了用细胞周期蛋白依赖性激酶抑制剂治疗癌症，必须确定合适的靶细胞群。通过靶向正常细胞群体的生长来抑制肿瘤的形成可能具有更可预测的优势，并且不太容易被肿瘤克隆中的突变所逃脱。

DESCRIPTION (provided by applicant): Models of tumor suppression by cell cycle growth inhibitors commonly assume that the critical inhibitory activity is intrinsic to the tumor clone. The recent discovery of tumor suppressor genes which are incapable of fully suppressing neoplastic growth with loss of only a single gene copy (i.e. haploid insufficient tumor suppression) in mouse models raises the possibility of alternative, non cell-autonomous mechanisms of tumor suppression. For example, loss of cell cycle inhibitor expression in cells extrinsic to the neoplastic clone may enhance cell growth by signals mediated through extracellular contact, paracrine factors, or angiogenesis. This project will further our understanding of the mechanism of tumor suppression by the CDK inhibitor p27Kipl and several interacting molecules. The studies will create targeted mutations in the mouse in which p27 is either deleted or activated in specific tissues. These novel gene mutations will then be combined with well defined murine models of induced carcinogenesis and gene expression analysis to define the mechanism of tumor suppression of p27 and its biochemical effects in tumorigenesis. By developing mice which harbor cell cycle gene mutations confined to the pituitary or thymus it will be determined whether the p27Kip 1 can induce adenomas and lymphomas in these tissues in a cell autonomous fashion, that is independent of the influence of factors from surrounding cells or tissues. In each model system the mechanism of tumor suppression by p27 will be further defined and the patterns of altered gene expression and cell cycle protein function will be characterized. In order to treat cancer with inhibitors of cyclin dependent kinases it is essential to identify the appropriate target cell population. Inhibition of tumorigenesis by targeting growth of normal cell populations may have the advantage of being more predictable and less prone to escape by mutations in the tumor clone.